Der erste Bericht über eine Antitumoraktiviträt von Extrakten von Boswellia serrata stammt von Jing und Mitarbeitern (1992) unter Verwendung von menschlichen HL 60 Leukämiezellen.
Untersuchungen, die 1999 in Tübingen durchgeführt wurden, zeigten ebenfalls eine Antitumorwirkung bei HL 60 Leukämiezellen sowie bei Glioblastomzellen. Es stellte sich jedoch bei all diesen Untersuchungen heraus, dass die in vitro verwendeten Konzentrationen von Boswelliaextrakten und Boswelliasäuren, die zur Hemmung des Tumorwachstums notwendig waren, wesentlich höher lagen als diejenigen, die eine Hemmung der Leukotriensynthese in Leukozyten bewirkten, wie dies auch aus der Tabelle hervorgeht. Andererseits ist es jedoch denkbar, dass niedrigere Konzentrationen von Boswelliasäuren bei solchen Tumoren wirksam sein könnten, die eng mit einer erhöhten Bildung von Leukotrien verbunden sind.
| 1. |
S670, an amide derivative of 3-O-acetyl-11-keto-β-boswellic acid, induces ferroptosis in human glioblastoma cells by generating ROS and inhibiting STX17-mediated fusion of autophagosome and lysosome.
Yang YH, Li W, Ren LW, Yang H, Zhang YZ, Zhang S, Hao Y, Yu DK, Tong RS, Du GH, Shi JY, Wang JH
Glioblastoma (GBM) is the most common malignant tumor in the brain with temozolomide (TMZ) as the only approved chemotherapy agent. GBM is characterized by susceptibility to radiation and chemotherapy resistance and recurrence as well as low immunological response. There is an urgent need for new therapy to improve the outcome of GBM patients. We previously reported that 3-O-acetyl-11-keto-β-boswellic acid (AKBA) inhibited the growth of GBM. In this study we characterized the anti-GBM effect of S670, a synthesized amide derivative of AKBA, and investigated the underlying mechanisms. We showed that S670 dose-dependently inhibited the proliferation of human GBM cell lines U87 and U251 with IC values of around 6 μM. Furthermore, we found that S670 (6 μM) markedly stimulated mitochondrial ROS generation and induced ferroptosis in the GBM cells. Moreover, S670 treatment induced ROS-mediated Nrf2 activation and TFEB nuclear translocation, promoting protective autophagosome and lysosome biogenesis in the GBM cells. On the other hand, S670 treatment significantly inhibited the expression of SXT17, thus impairing autophagosome-lysosome fusion and blocking autophagy flux, which exacerbated ROS accumulation and enhanced ferroptosis in the GBM cells. Administration of S670 (50 mg·kg·d, i.g.) for 12 days in a U87 mouse xenograft model significantly inhibited tumor growth with reduced Ki67 expression and increased LC3 and LAMP2 expression in the tumor tissues. Taken together, S670 induces ferroptosis by generating ROS and inhibiting STX17-mediated fusion of autophagosome and lysosome in GBM cells. S670 could serve as a drug candidate for the treatment of GBM.
Acta Pharmacol Sin. 2024 Jan;45(1):209-222.
PMID: 37749236 [PubMed - indexed for MEDLINE]
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| 2. |
Anti-cancer properties of boswellic acids: mechanism of action as anti-cancerous agent.
Trivedi VL, Soni R, Dhyani P, Sati P, Tejada S, Sureda A, Setzer WN, Faizal Abdull Razis A, Modu B, Butnariu M, Sharifi-Rad J
With the advent of highly effective plant-based medications with few or no side effects, the use of phytomedicines against complex diseases such as cancer is becoming more widespread. The broadly recognized pentacyclic triterpenes known as boswellic acids (BAs) are derived from the oleogum resin, or frankincense, extracted from the plant species of the genus . The frankincense mixture contains various BA types, each having a different potential and helping treat certain cancers. This review focuses on details regarding the traits of the BAs, their roles as anti-cancer agents, the mechanism underlying their activities, and the function of their semi-synthetic derivatives in managing and treating certain cancers. The review also explores the biological sources of BAs, how they are conserved, and how biotechnology might help preserve and improve BA production. The review concludes that the BAs and their semi-synthetic derivatives are effective against a broad spectrum of cancer cell lines. The detailed information in the review can be helpful for researchers to gain more information about BAs and BA-based medications for efficient and cost-effective cancer treatments.
Front Pharmacol. 2023;14():1187181.
PMID: 37601048 [PubMed - as supplied by publisher]
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| 3. |
Anti-cancer effect of nano-encapsulated boswellic acids, curcumin and naringenin against HepG-2 cell line.
Elnawasany S, Haggag YA, Shalaby SM, Soliman NA, El Saadany AA, Ibrahim MAA, Badria F
BACKGROUND: liver cancer is one of the most common cancers in the world. So far, there is no gold standard treatment for hepatocellular carcinoma. We conducted this in vitro study to assess the effect of three natural products: Boswellic acids, curcumin and naringin versus corresponding nanoparticles (NPs) on Hep G2 cells proliferation.
METHODS: Boswellic acid, curcumin, naringin-loaded NPs were prepared using nanoprecipitation method. Human liver (HepG2) cell line was cultured in Dulbecco's modified Eagle's medium (DMEM). The cell growth inhibition and cytotoxicity were evaluated by MTT assay.
RESULTS: Boswellic acid, curcumin, naringin were able to inhibit HepG2 cells proliferation. IC50 at 24 h, 48 h showed significant lower values in NPs versus Free herbs. IC50 values of free Boswellic acids and NPs at 24 h were (24.60 ± 1.89 and 7.78 ± 0.54, P < 0.001), at 48 h were (22.45 ± 1.13 and 5.58 ± 0.27, P < 0.001) respectively. IC50 values of free curcumin and NPs at 24 h were (5.89 ± 0.8 and 3.46 ± 0.23, P < 0.05), at 48 h were (5.57 ± 0.94 and 2.51 ± 0.11, P < 0.05), respectively. For free and naringenin NPs, IC50 values at 24 h were (14.57 ± 1.78 and 7.25 ± 0.17, P < 0.01), at 48 h were (11.37 ± 1.45 and 5.21 ± 0.18, P < 0.01) respectively.
CONCLUSION: Boswellic acid, curcumin, naringin and their nanoprecipitation prepared nanoparticles suppressed Hep G2 cells proliferation.
BMC Complement Med Ther. 2023 Jul;23(1):270.
PMID: 37516826 [PubMed - indexed for MEDLINE]
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| 4. |
Antiproliferative and cell cycle arrest potentials of 3-O-acetyl-11-keto-β-boswellic acid against MCF-7 cells in vitro.
Ahmed SA, Al-Shanon AF, Al-Saffar AZ, Tawang A, Al-Obaidi JR
INTRODUCTION: Cancer is a major issue in medical science with increasing death cases every year worldwide. Therefore, searching for alternatives and nonorthodox methods of treatments with high efficiency, selectivity and less toxicity is the main goal in fighting cancer. Acetyl-11-keto-β-boswellic acid (AKBA), is a derivative pentacyclic triterpenoid that exhibited various biological activities with potential anti-tumoral agents. In this research, AKBA was utilized to examine the potential cytotoxic activity against MCF-7 cells in vitro and monitor the cellular and morphological changes with a prospective impact on apoptosis induction.
METHODS: The cytotoxic activity of AKBA was measured by 3(4,5dimethylthiazole- 2-yl)-2,5 diphyneltetrazolium bromide (MTT) assay. A dose-dependent inhibition in MCF-7 cell viability was detected. The clonogenicity of MCF-7 cells was significantly suppressed by AKBA increment in comparison with untreated cells.
RESULT: Morphologically, exposure of MCF-7 cells to high AKBA concentrations caused changes in cell nuclear morphology which was indicated by increasing in nuclear size and cell permeability intensity. The mitochondrial membrane potential (ΔΨm) was reduced by increasing AKBA concentration with a significant release of cytochrome c. Acridine orange/ethidium bromide dual staining experiment confirmed that MCF-7 cells treated with AKBA (IC50 concentration) displayed a late stage of apoptosis indicated by intense and bright reddish colour.
CONCLUSION: A significant increase in reactive oxygen species formation was observed. Caspase 8 and caspase 9 activities were estimated and AKBA activated the production of caspase 8 and caspase 9 in a dose-dependent pattern. Finally, the cell phase distribution analysis was conducted, and flow cytometric analysis showed that AKBA at 200 μg mL-1 significantly arrest MCF-7 cells at the G1 phase and triggered apoptosis.
J Genet Eng Biotechnol. 2023 Jul;21(1):75.
PMID: 37393563 [PubMed - as supplied by publisher]
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| 5. |
Natural Anticancer Agents: Their Therapeutic Potential, Challenges,s and Promising Outcomes.
Tauro S, Dhokchawle B, Mohite P, Nahar D, Nadar S, Coutinho E
Cancer, the second leading cause of death worldwide, is a major health problem. Chemotherapy, radiation therapy and surgery are current treatments for cancer. Most anticancer drugs have severe toxic effects and are required to be administered in cycles to reduce toxicity and prevent resistance. Plant-based drugs have shown a potential for treatment of cancer, and various plant secondary metabolites have shown promising antitumor activity against several cancer cell lines, such as leukemia, colon cancer, prostate cancer, breast cancer and lung cancer. Vincristine, etoposide, topotecan and paclitaxel, which are of natural origin, are successfully used in clinical practice, and this has generated interest in natural compounds as anticancer agents. Some phytoconstituents like curcumin, piperine, allicin, quercetin and resveratrol have been extensively researched and reviewed. In the current study, we have reviewed several plants like Athyrium hohenackerianum, Aristolochia baetica, Boswellia serrata, Panax ginseng, Berberis vulgaris, Tanacetum parthenium, Glycine max, Combretum fragrans, Persea americana, Raphanus sativus, Camellia sinensis, and Nigella sativa for their source, key phytoconstituents, and anticancer activity along with their toxicity profile. Few phytoconstituents like boswellic acid, sulforaphane and ginsenoside showed excellent anticancer activity compared to standard drugs and are potential clinical candidates.
Curr Med Chem. 2023 May;():.
PMID: 37138435 [PubMed - as supplied by publisher]
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Metabolomics-based discovery of XHP as a CYP3A4 inhibitor against pancreatic cancer.
Yang Y, Guo Y, Luo H, Wang M, Chen F, Cui H, Chen P, Yin Z, Li L, Dai Y, Zeng J, Zhao J
Xihuang Wan (XHW), a purgative and detoxifying agent, is commonly utilized in modern medicine as a treatment and adjuvant therapy for various malignancies, including breast cancer, liver cancer, and lung cancer. A clinical study demonstrated the potential usefulness of the combination of XHW and gemcitabine as a therapy for pancreatic cancer (PC), indicating that XHW's broad-spectrum antitumor herbal combination could be beneficial in the treatment of PC. However, the precise therapeutic efficacy of XHW in treating pancreatic cancer remains uncertain. This study assessed the biological activity of XHW by optimizing the therapeutic concentration of XHW (Xihuang pills, XHP). We performed cell culture and developed an animal test model to determine whether XHP can inhibit pancreatic cancer (PC). We also applied the well-known widely targeted metabolomics analysis and conducted specific experiments to assess the feasibility of our method in PC therapy. We used UPLC/Q-TOF-MS to test XHP values to set up therapeutic concentrations for the test model. SW1990 pancreatic cancer cells were cultured to check the effect the anti-cancer effects of XHP by general cell analyses including CCK-8, Hoechst 33258, and flow cytometry. To develop the animal model, a solid tumor was subcutaneously formed on a mouse model of PC and assessed by immunohistochemistry and TUNEL apoptosis assay. We also applied the widely targeted metabolomics method following Western blot and RT-PCR to evaluate multiple metabolites to check the therapeutic effect of XHP in our cancer test model. Quantified analysis from UPLC/Q-TOF-MS showed the presence of the following components of XHP: 11-carbonyl-β-acetyl-boswellic acid (AKBA), 11-carbonyl-β-boswellic acid (KBA), 4-methylene-2,8,8-trimethyl-2-vinyl-bicyclo [5.2.0]nonane, and (1S-endo)-2-methyl-3-methylene-2-(4-methyl-3-3-pentenyl)-bicyclo [2.2.1heptane]. The results of the cell culture experiments demonstrated that XHP suppressed the growth of SW1990 PC cells by enhancing apoptosis. The results of the animal model tests also indicated the suppression effect of XHP on tumor growth. Furthermore, the result of the widely targeted metabolomics analysis showed that the steroid hormone biosynthesis metabolic pathway was a critical factor in the anti-PC effect of XHP in the animal model. Moreover, Western blot and RT-PCR analyses revealed XHP downregulated CYP3A4 expression as an applicable targeted therapeutic approach. The results of this study demonstrated the potential of XHP in therapeutic applications in PC. Moreover, the widely targeted metabolomics method revealed CYP3A4 is a potential therapeutic target of XHP in PC control. These findings provide a high level of confidence that XHP significantly acts as a CYP3A4 inhibitor in anti-cancer therapeutic applications.
Front Pharmacol. 2023;14():1164827.
PMID: 37081969 [PubMed - as supplied by publisher]
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| 7. |
ADME Prediction, Structure-activity Relationship of Boswellic Acid Scaffold for the Aspect of Anticancer & Anti-inflammatory Potency.
Kumar A, Sharma S, Mishra S, Ojha S, Upadhyay P
Nature is the chief source of various remedies which are used to cure various diseases. Boswellic acid (BA) is a secondary metabolite from the pentacyclic terpenoid compound groups that are derived from the plant genus Boswellia. The oleo gum resins of these plants are primarily composed of polysaccharides, with the remaining amounts of resin (30-60%) and essential oils (5-10%) soluble in organic solvents. BA and its analogs are also reported to exhibit various in vivo and biological responses for example anti-inflammatory, anti-tumor, free radical scavenging activity, etc. Among all analogs, 11-keto-β-boswellic acid (KBA) and 3-O-acetyl-11-keto-β-boswellic acid (AKBA) has been demonstrated to be the most effective at reducing cytokine production and inhibiting the inflammatory responsecausing enzymes. In this review, we summarized the computational ADME prediction via the SwissADME computational tool and the structure-activity relationship of the Boswellic acid scaffold for the aspect of anticancer and antiinflammatory potency. In addition to these research findings which are associated with the therapy of acute inflammation and some cancers, the potential of boswellic acids against other disorders was also discussed.
Anticancer Agents Med Chem. 2023;23(13):1499-1505.
PMID: 37070442 [PubMed - indexed for MEDLINE]
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| 8. |
[Comparison of in vivo plasma pharmacokinetics and urine excretion of main components in Xihuang Formula in rats with precancerous lesions of breast cancer].
Xie JX, Zhang YJ, Huang PW, Zhang YT, Wang Z, Feng NP
The UPLC-MS/MS was established for the determination of acetyl-11-keto-beta-boswellic acid(AKBA) and β-boswellic acid(β-BA), the main active components of Olibanum and Myrrha extracts in Xihuang Formula, in rat plasma and urine. The effects of compatibility on the pharmacokinetic behaviors of AKBA and β-BA in rats were investigated, and the differences in pharmacokinetic behaviors between healthy rats and rats with precancerous lesions of breast cancer were compared. The results showed that compared with RM-NH and RM-SH groups, the AUC_(0-t) and AUC_(0-∞) of β-BA increased(P<0.05 or P<0.01), T_(max) decreased(P<0.05 or P<0.01), and C_(max) increased(P<0.01) after compatibility. The trends of AKBA and β-BA were the same. Compared with RM-SH group, the T_(max) decreased(P<0.05), C_(max) increased(P<0.01), and the absorption rate increased in the normal group of Xihuang Formula. The results of urinary excretion showed that there was a decreasing trend in the urinary excretion rate and total urinary excretion of β-BA and AKBA after compatibility, but there was no statistical difference. Compared with normal group of Xihuang Formula, the AUC_(0-t) and AUC_(0-∞) of β-BA increased(P<0.05), T_(max) increased(P<0.05), and the clearance rate decreased in the breast precancerous lesion group. AUC_(0-t) and AUC_(0-∞) of AKBA showed an increasing trend, the in vivo retention time was prolonged, and the clearance rate was reduced, but there was no significant difference compared with the normal group. The cumulative urinary excretion and urinary excretion rate of β-BA and AKBA decreased under pathological conditions, indicating that pathological conditions could affect the in vivo process of β-BA and AKBA, and reduce their excretion in the form of prototype drugs, showing different pharmacokine-tic characteristics from normal physiological conditions. In this study, UPLC-MS/MS analysis method was established, which was sui-table for in vivo pharmacokinetic analysis of β-BA and AKBA. This study laid a foundation for the development of new dosage forms of Xihuang Formula.
Zhongguo Zhong Yao Za Zhi. 2023 Mar;48(6):1642-1651.
PMID: 37005852 [PubMed - indexed for MEDLINE]
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| 9. |
Essential Oils Extracted from Oleo Gum Resin Loaded into PLGA-PCL Nanoparticles: Enhanced Cytotoxic and Apoptotic Effects against Breast Cancer Cells.
Azzazy HME, Abdelnaser A, Al Mulla H, Sawy AM, Shamma SN, Elhusseiny M, Alwahibi S, Mahdy NK, Fahmy SA
This work aims to develop and optimize blended polylactide--glycolide (PLGA) and poly(ε-caprolactone, PCL) loaded with oil (BO) to improve BO's physicochemical properties and anti-breast cancer effects enhancing apoptosis. In this context, BO was extracted from oleo gum resins (BO) hydrodistillation and chemically characterized by evaluating its essential oil's composition using gas chromatography-mass spectrometry. Then, BO/PLGA-PCL NPs were formulated using the emulsion (O/W) solvent evaporation technique using a PLGA-PCL mixture at five different ratios (1:1, 2:1, 3:1, 1:2, and 1:3, respectively). The optimized NPs had a spherical morphology with no agglomerations and the lowest hydrodynamic size (230.3 ± 3.7 nm) and polydispersity index (0.13 ± 0.03) and the highest ζ potential (-20.36 ± 4.89 mV), as compared to the rest of the formulas. PLGA-PCL NPs could entrap 80.59 ± 3.37% of the BO and exhibited a controlled, sustained release of BO (83.74 ± 3.34%) over 72 h. Encapsulating BO in the form of BO/PLGA-PCL NPs resulted in a lower IC value as assessed by the MTT assay. Furthermore and upon assessing the apoptotic effect of both BO and BO/PLGA-PCL NPs, there was an increase in the percentage of apoptotic and necrotic cell percentages compared to the control and free BO. Encapsulation of BO in PLGA-PCL NPs doubled the percentage of apoptotic and necrotic cells exerted by free BO. These findings support the potential use of BO/PLGA-PCL NPs in treating breast cancer.
ACS Omega. 2023 Jan;8(1):1017-1025.
PMID: 36643489 [PubMed - as supplied by publisher]
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| 10. |
Synergistic Effect of HAD-B1 and Afatinib Against Gefitinib Resistance of Non-Small Cell Lung Cancer.
Song SY, Park JH, Park SJ, Kang IC, Yoo HS
In epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC), acquired resistance to EGFR tyrosine kinase inhibitors (TKI) leads to disease progression. Strategies to overcome the resistance are required in treatment for advanced lung cancer. In this study, we investigated the therapeutic effect of afatinib and HangAmDan-B1 (HAD-B1) co-administration in gefitinib-resistant NSCLC using HCC827-GR, NSCLC cell line with gefitinib resistance, and the HCC827-GR cell implanted mouse model. HAD-B1 consists of 4 herbs, Radix, , C. A. Mey, and Birdwood, and has been reported to be effective in patients with advanced lung cancer in clinical practice. Our findings demonstrated that HAD-B1 combined with afatinib markedly inhibited cell proliferation and induced apoptosis compared to afatinib monotherapy and HAD-B1 monotherapy. Inhibition of HCC827-GR cell proliferation by HAD-B1 occurred through MET amplification and reduced phosphorylation, and the synergistic effect of afatinib and HAD-B1 induced cell cycle arrest and apoptosis in HCC827-GR cells via the downregulation of ERK and mTOR signaling pathways. In hematology and biochemistry tests, HAD-B1 alleviated the toxicity of tumor. In conclusion, HAD-B1 combined with afatinib would be a promising therapeutic strategy for NSCLC with EGFR-TKI resistance.
Integr Cancer Ther. 2022;21():15347354221144311.
PMID: 36565160 [PubMed - indexed for MEDLINE]
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| 11. |
Comparative study of the cytotoxicity, apoptotic, and epigenetic effects of Boswellic acid derivatives on breast cancer.
Jamshidi-Adegani F, Ghaemi S, Al-Hashmi S, Vakilian S, Al-Kindi J, Rehman NU, Alam K, Al-Riyami K, Csuk R, Arefian E, Al-Harrasi A
This study aimed to compare the effect of Boswellic acid derivatives on the viability, apoptosis, and epigenomic profiling of breast cancer. According to the viability assays, 3-O-acetyl-11-keto-β-Boswellic acid (AKBA) showed more toxicity against MDA-MB-231 cells when compared with the 3-O-acetyl-β-Boswellic acid (ABA). In contrast, ABA revealed less toxicity against MCF-10A. Cell cycle and apoptosis assays determined the maximum apoptotic effect of AKBA on MCF-7, and MDA-MB-231 cells. Interestingly, β-Boswellic acid (BA) and ABA did not promote the apoptosis in MCF-10A cells. Transwell migration assay indicated the greatest normalized inhibition (around 160%) in the migration of MDA-MB-231 cells induced by AKBA. The expression of P53, BAX, and BCL2 genes in cancerous cell lines has affirmed that both AKBA and ABA could induce the maximal apoptosis. Western-blot investigation demonstrated that the maximum over-expression of P53 protein (1.96 times) was caused by AKBA in MDA-MB-231 cells, followed by ABA in MCF-7 cells. The BCL2 protein expression was in agreement with the previously reported results. The global DNA methylation in both cancerous cells was reduced by ABA. These results suggest that ABA represented more epigenetic modulatory effect while AKBA shows more cytotoxic and apoptotic effect against breast cancer cell lines.
Sci Rep. 2022 Nov;12(1):19979.
PMID: 36411309 [PubMed - indexed for MEDLINE]
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| 12. |
AKBA inhibits radiotherapy resistance in lung cancer by inhibiting maspin methylation and regulating the AKT/FOXO1/p21 axis.
Gong C, Li W, Wu J, Li YY, Ma Y, Tang LW
Acetyl-keto-b-boswellic acid (AKBA) functions in combating human malignant tumors, including lung cancer. However, the function of AKBA in regulating the radioresistance of lung cancer and its underlying mechanism still need to be elucidated. Radiation-resistant lung cancer cells (RA549) were established. Quantitative real-time polymerase chain reaction (QRT-PCR) and Western blot were employed to examine the messenger RNA (mRNA) and protein expressions. After being treated with AKBA and different doses of X-ray, cell proliferation and survival were examined using colony formation assay and cell-counting kit-8 (CCK-8) assay. The cellular localization of Forkhead box 1 (FOXO1) was measured by immunofluorescence (IF). Flow cytometry was employed to analyze cell cycle and apoptosis. In addition, in vivo experiment was performed to determine the effect of AKBA on the sensitivity of tumors to radiation. Herein, we found that AKBA could enhance the radiosensitivity in RA549, suppress cell proliferation, induce cell apoptosis and arrest cell cycle. It was observed that maspin was lowly expressed and hypermethylated in RA549 cells compared to that in A549 cells, while these changes were all eliminated by AKBA treatment. Maspin knockdown could reverse the regulatory effects of AKBA on radioresistance and cellular behaviors of RA549 cells. In addition, we found that AKBA treatment could repress the phosphorylation of Serine/Threonine Kinase (AKT), and FOXO1, increase the translocation of FOXO1 and p21 level in RA549 cells, which was abolished by maspin knockdown. Moreover, results of tumor xenograft displayed that AKBA could enhance the sensitivity of tumor to radiation through the maspin/AKT/FOXO1/p21 axis. We discovered that AKBA enhanced the radiosensitivity of radiation-resistant lung cancer cells by regulating maspin-mediated AKT/FOXO1/p21 axis.
J Radiat Res. 2023 Jan;64(1):33-43.
PMID: 36300343 [PubMed - indexed for MEDLINE]
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| 13. |
Anti-proliferative tirucallane triterpenoids from gum resin of Boswellia sacra.
Zhang B, Liu D, Cao S, Yao T, Liu G, Chen L, Qiu F
Eight new tirucallane triterpenoids (1-2, 5-10) along with two known compounds (3-4) were isolated from the gum resin of Boswellia sacra. Their structures were elucidated by extensive physicochemical and spectroscopic analysis, as well as computational calculations, and single crystal X-ray diffraction. Spirosacraoic acid A (1) and B (2), possess an unusual 6/5/6/5 rearranged spirocyclic carbon skeleton. All the isolates were evaluated for their anti-proliferative activity against two tumor cell lines (HepG2 and HCT-116 cells). Compound 10 displayed remarkable inhibitory activity against HepG2 cells in a dose-dependent manner with the IC value of 28.01 μM. High content analysis (HCA) showed that 10 induces apoptosis in HepG2 cells. The western blotting results revealed that 10 could up-regulate the ratio of the expression of Bax/BCL-2, and promote the caspase 3 activation and PARP cleavage. Mechanically, molecular modeling studies demonstrated that 10 could dock into EGFR active site. Meanwhile 10 significantly decreased the protein expression of p-EGFR. Furthermore, inhibition of EGFR by addition of EGFR siRNA enhanced the growth inhibitory effects of 10 on HepG2 cells, indicating that the anti-tumor effect of 10 on HepG2 cells was mediated by inhibition of EGFR.
Bioorg Chem. 2022 Dec;129():106155.
PMID: 36209562 [PubMed - indexed for MEDLINE]
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| 14. |
Retraction: Boswellic Acid Suppresses Growth and Metastasis of Human Pancreatic Tumors in an Orthotopic Nude Mouse Model through Modulation of Multiple Targets.
PLoS One. 2022;17(9):e0275582.
PMID: 36170284 [PubMed - as supplied by publisher]
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| 15. |
Selective anti-cancer activity against melanoma cells using 3--acetyl-β-boswellic acid-loaded 3D-Printed scaffold.
Jamshidi-Adegani F, Vakilian S, Al-Hashmi S, Al-Kindi J, Rehman NU, Al-Sinani Y, Ghaemi S, Alam K, Anwar MU, Csuk R, Al-Harrasi A
This study aimed to develop a local 3 D-printed bioactive graft using poly-caprolacton (PCL) as a drug carrier and 3--acetyl-β-boswellic acid (β-ABA) as an anticancer compound. β-ABA-loaded 3 D-printed scaffold was fabricated and physically characterized. The results indicated more desirable mechanical and physical properties of the β-ABA-loaded PCL mat in comparison with the PCL scaffold. Following sustained release of β-ABA, the β-ABA-loaded PCL scaffold revealed selective cytotoxic activity against melanoma cells, while the PCL + ABA with the bolus delivery of β-ABA was toxic against fibroblast cells. Followed by the induction of apoptosis in melanoma cells at the gene level, the result of the western blot showed that the β-ABA-loaded scaffold significantly up-regulated P53 and down-regulated BCL2, with an increment in the ratio of Bax/BCL2. The selective anti-cancer properties of β-ABA-loaded 3 D printed scaffold against melanoma cells indicated that this scaffold could be potentially used as a bioactive graft to improve the melanoma treatment.
Nat Prod Res. 2023 Jun;37(12):2049-2054.
PMID: 36008779 [PubMed - indexed for MEDLINE]
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| 16. |
Correction: 3-O-acetyl-11-keto-β-boswellic acid exerts anti-tumor effects in glioblastoma by arresting cell cycle at G2/M phase.
Li W, Liu J, Fu W, Zheng X, Ren L, Liu S, Wang J, Ji T, Du G
J Exp Clin Cancer Res. 2022 Aug;41(1):236.
PMID: 35918768 [PubMed - as supplied by publisher]
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| 17. |
β-Boswellic Acid Suppresses Breast Precancerous Lesions GLUT1 Targeting-Mediated Glycolysis Inhibition and AMPK Pathway Activation.
Bie F, Zhang G, Yan X, Ma X, Zhan S, Qiu Y, Cao J, Ma Y, Ma M
Breast carcinoma is a multistep progressive disease. Precancerous prevention seems to be crucial. β-Boswellic acid (β-BA), the main component of the folk medicine (), has been reported to be effective in various diseases including tumors. In this work, we demonstrated that β-BA could inhibit breast precancerous lesions in rat disease models. Consistently, β-BA could suppress proliferation and induce apoptosis on MCF-10AT without significantly influencing MCF-10A. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis suggested that β-BA may interfere with the metabolic pathway. Metabolism-related assays showed that β-BA suppressed glycolysis and reduced ATP production, which then activated the AMPK pathway and inhibited the mTOR pathway to limit MCF-10AT proliferation. Further molecular docking analysis suggested that GLUT1 might be the target of β-BA. Forced expression of GLUT1 could rescue the glycolysis suppression and survival limitation induced by β-BA on MCF-10AT. Taken together, β-BA could relieve precancerous lesions and through GLUT1 targeting-induced glycolysis suppression and AMPK/mTOR pathway alterations. Here, we offered a molecular basis for β-BA to be developed as a promising drug candidate for the prevention of breast precancerous lesions.
Front Oncol. 2022;12():896904.
PMID: 35712503 [PubMed - as supplied by publisher]
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| 18. |
Phytotherapy in Integrative Oncology-An Update of Promising Treatment Options.
Zimmermann-Klemd AM, Reinhardt JK, Winker M, Gründemann C
Modern phytotherapy is part of today's conventional evidence-based medicine and the use of phytopharmaceuticals in integrative oncology is becoming increasingly popular. Approximately 40% of users of such phytopharmaceuticals are tumour patients. The present review provides an overview of the most important plants and nature-based compounds used in integrative oncology and illustrates their pharmacological potential in preclinical and clinical settings. A selection of promising anti-tumour plants and ingredients was made on the basis of scientific evidence and therapeutic practical relevance and included Boswellia, gingko, ginseng, ginger, and curcumin. In addition to these nominees, there is a large number of other interesting plants and plant ingredients that can be considered for the treatment of cancer diseases or for the treatment of tumour or tumour therapy-associated symptoms. Side effects and interactions are included in the discussion. However, with the regular and intended use of phytopharmaceuticals, the occurrence of adverse side effects is rather rare. Overall, the use of defined phytopharmaceuticals is recommended in the context of a rational integrative oncology approach.
Molecules. 2022 May;27(10):.
PMID: 35630688 [PubMed - indexed for MEDLINE]
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| 19. |
Bioactive Evaluation of Ursane-Type Pentacyclic Triterpenoids: -Boswellic Acid Interferes with the Glycosylation and Transport of Intercellular Adhesion Molecule-1 in Human Lung Adenocarcinoma A549 Cells.
Nakano K, Sasaki S, Kataoka T
Ursane-type pentacyclic triterpenoids exert various biological effects, including anticancer and anti-inflammatory activities. We previously reported that ursolic acid, corosolic acid, and asiatic acid interfered with the intracellular trafficking and glycosylation of intercellular adhesion molecule-1 (ICAM-1) in human lung adenocarcinoma A549 cells stimulated with the pro-inflammatory cytokine interleukin-1α. However, the structure-activity relationship of ursane-type pentacyclic triterpenoids remains unclear. In the present study, the biological activities of seven ursane-type pentacyclic triterpenoids (-boswellic acid, uvaol, madecassic acid, 3--acetyl-11-keto--boswellic acid, ursolic acid, corosolic acid, and asiatic acid) were investigated. We revealed that the inhibitory activities of ursane-type pentacyclic triterpenoids on the cell surface expression and glycosylation of ICAM-1 and α-glucosidase activity were influenced by the number of hydroxy groups and/or the presence and position of a carboxyl group. We also showed that -boswellic acid interfered with ICAM-1 glycosylation in a different manner from other ursane-type pentacyclic triterpenoids.
Molecules. 2022 May;27(10):.
PMID: 35630550 [PubMed - indexed for MEDLINE]
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| 20. |
2-Pyridin-4-yl-methylene-beta-boswellic Acid-A Potential Candidate for Targeting O-Methylguanine-DNA Methyltransferase Epi-transcriptional Reprogramming in KRAS G13D-Microsatellite Stable, G12V-Microsatellite Instable Mutant Colon Cancer.
Qayum A, Singh J, Kumar A, Shah SM, Srivastava S, Kushwaha M, Magotra A, Nandi U, Malik R, Shah BA, Singh SK
PMBA (2-Pyridin-4-yl-methylene-beta-boswellic acid), screened from among the 21 novel series of semisynthetic analogues of β-boswellic acid, is being presented as a lead compound for integrative management of KRAS mutant colorectal cancer (CRC), upon testing and analysis for its anticancerous activity on a panel of NCI-60 cancer cell lines and in vivo models of the disease. PMBA (1.7-29 μM) exhibited potent proliferation inhibition on the cell lines and showed sensitivity in microsatellite instability and microsatellite stable (GSE39582 and GSE92921) subsets of KRAS gene (Kirsten rat sarcoma viral oncogene homolog)-mutated colon cell lines, as revealed via flow cytometry analysis. A considerable decrease in mitogen-activated protein kinase pathway downstream effectors was observed in the treated cell lines via the western blot and STRING (Search tool for the retrieval of interacting genes/proteins) analysis. PMBA was further found to target KRAS at its guanosine diphosphate site. Treatment of the cell lines with PMBA showed significant reduction in MGMT promoter methylation but restored MGMT (O-methylguanine-DNA methyltransferase) messenger ribonucleic acid expression via significant demethylation of the hypermethylated CpG (Cytosine phosphate guanine) sites in the MGMT promoter. A significant decrease in dimethylated H3K9 (Dimethylation of lysine 9 on histone 3) levels in the MGMT promoter in DNA hypo- and hypermethylated HCT-116 and SW-620 cells was observed after treatment. In the MNU (-methyl--nitrosourea)-induced CRC in vivo model, PMBA instillation restricted and repressed polyp formation, suppressed tumor proliferation marker Ki67 (Marker of proliferation), ablated KRAS-associated cytokine signaling, and decreased mortality. Clinical trial data for the parent molecule revealed its effectiveness against the disease, oral bioavailability, and system tolerance. Comprehensively, PMBA represents a new class of KRAS inhibitors having a therapeutic window in the scope of a drug candidate. The findings suggest that the PMBA analogue could inhibit the growth of human CRC in vivo through downregulation of cancer-associated biomarkers as well as reactivate expression of the MGMT gene associated with increased H3K9 acetylation and H3K4 methylation with facilitated transcriptional activation, which might be important in silencing of genes associated with upregulation in the activity of KRAS.
ACS Pharmacol Transl Sci. 2022 May;5(5):306-320.
PMID: 35592435 [PubMed - as supplied by publisher]
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| 21. |
Xihuang pills induce apoptosis in hepatocellular carcinoma by suppressing phosphoinositide 3-kinase/protein kinase-B/mechanistic target of rapamycin pathway.
Teng YJ, Deng Z, Ouyang ZG, Zhou Q, Mei S, Fan XX, Wu YR, Long HP, Fang LY, Yin DL, Zhang BY, Guo YM, Zhu WH, Huang Z, Zheng P, Ning DM, Tian XF
BACKGROUND: The phosphoinositide 3-kinase/protein kinase-B/mechanistic target of rapamycin (PI3K/Akt/mTOR) signalling pathway is crucial for cell survival, differentiation, apoptosis and metabolism. Xihuang pills (XHP) are a traditional Chinese preparation with antitumour properties. They inhibit the growth of breast cancer, glioma, and other tumours by regulating the PI3K/Akt/mTOR signalling pathway. However, the effects and mechanisms of action of XHP in hepatocellular carcinoma (HCC) remain unclear. Regulation of the PI3K/Akt/mTOR signalling pathway effectively inhibits the progression of HCC. However, no study has focused on the XHP-associated PI3K/Akt/mTOR signalling pathway. Therefore, we hypothesized that XHP might play a role in inhibiting HCC through the PI3K/Akt/mTOR signalling pathway.
AIM: To confirm the effect of XHP on HCC and the possible mechanisms involved.
METHODS: The chemical constituents and active components of XHP were analysed using ultra-performance liquid chromatography-quadrupole time of flight mass spectrometry (UPLC-Q-TOF-MS). Cell-based experiments and xenograft tumour experiments were utilized to evaluate the effect of XHP on HCC tumorigenesis. First, SMMC-7721 cells were incubated with different concentrations of XHP (0, 0.3125, 0.625, 1.25, and 2.5 mg/mL) for 12 h, 24 h and 48 h. Cell viability was assessed using the CCK-8 assay, followed by an assessment of cell migration using a wound healing assay. Second, the effect of XHP on the apoptosis of SMMC-7721 cells was evaluated. SMMC-7721 cells were stained with fluorescein isothiocyanate and annexin V/propidium iodide. The number of apoptotic cells and cell cycle distribution were measured using flow cytometry. The cleaved protein and mRNA expression levels of caspase-3 and caspase-9 were detected using Western blotting and quantitative reverse-transcription polymerase chain reaction (RT-qPCR), respectively. Third, Western blotting and RT-qPCR were performed to confirm the effects of XHP on the protein and mRNA expression of components of the PI3K/Akt/mTOR signalling pathway. Finally, the effects of XHP on the tumorigenesis of subcutaneous hepatocellular tumours in nude mice were assessed.
RESULTS: The following 12 compounds were identified in XHP using high-resolution mass spectrometry: Valine, 4-gingerol, myrrhone, ricinoleic acid, glycocholic acid, curzerenone, 11-keto-β-boswellic acid, oleic acid, germacrone, 3-acetyl-9,11-dehydro-β-boswellic acid, 5β-androstane-3,17-dione, and 3-acetyl-11-keto-β-boswellic acid. The cell viability assay results showed that treatment with 0.625 mg/mL XHP extract decreased HCC cell viability after 12 h, and the effects were dose- and time-dependent. The results of the cell scratch assay showed that the migration of HCC cells was significantly inhibited in a time-dependent manner by the administration of XHP extract (0.625 mg/mL). Moreover, XHP significantly inhibited cell migration and resulted in cell cycle arrest and apoptosis. Furthermore, XHP downregulated the PI3K/Akt/mTOR signalling pathway, which activated apoptosis executioner proteins (, caspase-9 and caspase-3). The inhibitory effects of XHP on HCC cell growth were determined by analysing the tumour xenograft volumes and weights.
CONCLUSION: XHP inhibited HCC cell growth and migration by stimulating apoptosis the downregulation of the PI3K/Akt/mTOR signalling pathway, followed by the activation of caspase-9 and caspase-3. Our findings clarified that the antitumour effects of XHP on HCC cells are mediated by the PI3K/Akt/mTOR signalling pathway, revealing that XHP may be a potential complementary therapy for HCC.
World J Gastrointest Oncol. 2022 Apr;14(4):872-886.
PMID: 35582102 [PubMed - as supplied by publisher]
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| 22. |
Synergistic combination of PMBA and 5-fluorouracil (5-FU) in targeting mutant KRAS in 2D and 3D colorectal cancer cells.
Qayum A, Magotra A, Shah SM, Nandi U, Sharma PR, Shah BA, Singh SK
β-Boswellic acid (β-BA), a potent NF-kB signaling pathway inhibitor, has shown synergistic anti-cancerous activity (NCT03149081, NCT00243022 and NCT02977936) in various clinical trials as complementary therapies. The study has been conducted to investigate the effect and efficacy of 2-pyridin-4-yl methylene β-boswellic acid (PMBA) and 5-Flourouracil (5-FU) in combination therapy for the treatment of KRAS mutant colon cancer. Analysis of isobologram showed synergistic combination index (CI > 1) of PMBA and 5-FU against the HCT-116 and SW-620 cell lines. The growth-inhibiting PMBA also caused apoptosis mediating effects with dose-dependent increase in caspase-3 activity, while inhibiting the formation of colonies in combination with 5-FU. As evident, PMBA affected colorectal 3D CSC properties including the ability to self-renew along with the expression of multi-drug resistance genes, ., ABCB1, ABCC1 and ALDH1A1, ALDH1A2, ALDH1A3, ALDH3A1, and CSC markers like CD44, CD166, EPCAM, OCT-4, SOX-2, and NANOG compared with those in 2D model explaining the expression pattern of oncogenic KRAS mutation. When examined for plasma level of PMBA (20 mg) and PMBA+5-FU (20 + 40 mg), a time-dependent increase in the level of the drug (5-FU) was detected, indicating its absorption and bioavailability with excellent half-life of the PMBA for both routes of administration (IV and Oral), thereby indicating a new adjuvant therapy for KRAS mutant colon cancer.
Heliyon. 2022 Apr;8(4):e09103.
PMID: 35445157 [PubMed - as supplied by publisher]
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| 23. |
Protective role of AKBA against benzo(a)pyrene-induced lung carcinogenesis by modulating biotransformation enzymes and oxidative stress.
Bhardwaj P, Kumar M, Dhatwalia SK, Garg ML, Dhawan DK
The present study was designed to explore the chemopreventive potential of 3-acetyl-11-keto-β-boswellic acid (AKBA) during the initiation and promotion stage of lung carcinogenesis induced by benzo(a)pyrene (BaP) in female Sprague Dawley rats. BaP was administered at a dose level of 50 mg/kg b.wt. twice a week orally in olive oil for 4 weeks. AKBA administration was started 4 weeks before BaP treatment and continued for another 8 weeks at a dose level of 50 mg/kg b.wt. orally in olive oil three times a week. BaP treatment showed significantly increased in the activities of Phase I biotransformation enzymes (Cytochrome P , b , and aryl hydrocarbon hydrolase) and inhibited the activity of Phase II enzyme (glutathione-S-transferase). Also, a significant elevation in oxidative stress biomarkers lipid peroxidation, reactive oxygen species, and protein carbonyl content concentration. Further, an appreciable decrease was observed in the activities of endogenous antioxidant enzymes superoxide dismutase, CAT, GPx, GR, and a decline in nonenzymatic GSH levels. As a result of BaP induced oxidative stress, alteration in erythrocytes morphology was observed. Fourier transform infrared spectroscopy spectrum of lung tissue showed structural changes due to BaP exposure. Moreover, levels of tumor biomarkers such as total sialic acid, carcinoembryonic antigen, and alkaline phosphatase were significantly elevated following BaP treatment which was substantiated by alterations noticed in the histoarchitecture of lung tissue. Interestingly, AKBA administration to BaP treated rats appreciably alleviated the changes inflicted by BaP on various biochemical indices and histoarchitecture of lungs. Therefore, the study clearly revealed that AKBA by containing oxidative stress shall prove to be quite effective in providing chemoprevention against BaP induced lung carcinogenesis.
J Biochem Mol Toxicol. 2022 Jul;36(7):e23072.
PMID: 35437857 [PubMed - indexed for MEDLINE]
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| 24. |
Synthesis of 3--Acetyl-11-keto-β-boswellic Acid (AKBA)-Derived Amides and Their Mitochondria-Targeted Antitumor Activities.
Li C, He Q, Xu Y, Lou H, Fan P
In this study, we synthesized a series of amide and mitochondria-targeted derivatives with 3--acetyl-11-keto-β-boswellic acid (AKBA) as the parent structure and an ethylenediamine moiety as the link chain. Compound , a mitochondrial-targeting potential derivative, showed significantly stronger antitumor activity than that of AKBA, and it could induce vacuolization of A549 cells and stimulate the production of reactive oxygen species (ROS) in a time- and concentration-dependent manner. The antioxidant -acetylcysteine (NAC) could inhibit the ROS level but could not suppress vacuolization and cell death induced by . Further studies demonstrated that caused abnormal opening of mitochondrial permeability transition pore (MPTP) and a decrease of mitochondrial membrane potential; additionally, it caused cell cycle arrest in G/G but did not induce apoptosis. represented a compound with improved antiproliferative effects for cancer therapy working through new mechanisms.
ACS Omega. 2022 Mar;7(11):9853-9866.
PMID: 35350335 [PubMed - as supplied by publisher]
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| 25. |
Frankincense myrrh attenuates hepatocellular carcinoma by regulating tumor blood vessel development through multiple epidermal growth factor receptor-mediated signaling pathways.
Zheng P, Huang Z, Tong DC, Zhou Q, Tian S, Chen BW, Ning DM, Guo YM, Zhu WH, Long Y, Xiao W, Deng Z, Lei YC, Tian XF
BACKGROUND: In traditional Chinese medicine (TCM), frankincense and myrrh are the main components of the antitumor drug Xihuang Pill. These compounds show anticancer activity in other biological systems. However, whether frankincense and/or myrrh can inhibit the occurrence of hepatocellular carcinoma (HCC) is unknown, and the potential molecular mechanism(s) has not yet been determined.
AIM: To predict and determine latent anti-HCC therapeutic targets and molecular mechanisms of frankincense and myrrh .
METHODS: In the present study, which was based on the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (http://tcmspw.com/tcmsp.php), Universal Protein database (http://www.uniprot.org), GeneCards: The Human Gene Database (http://www.genecards.org/) and Comparative Toxicogenomics Database (http://www.ctdbase.org/), the efficacy of and mechanism by which frankincense and myrrh act as anti-HCC compounds were predicted. The core prediction targets were screened by molecular docking. , SMMC-7721 human liver cancer cells were transplanted as xenografts into nude mice to establish a subcutaneous tumor model, and two doses of frankincense plus myrrh or one dose of an EGFR inhibitor was administered to these mice continuously for 14 d. The tumors were collected and evaluated: the tumor volume and growth rate were gauged to evaluate tumor growth; hematoxylin-eosin staining was performed to estimate histopathological changes; immunofluorescence (IF) was performed to detect the expression of CD31, α-SMA and collagen IV; transmission electron microscopy (TEM) was conducted to observe the morphological structure of vascular cells; enzyme-linked immunosorbent assay (ELISA) was performed to measure the levels of secreted HIF-1α and TNF-α; reverse transcription-polymerase chain reaction (RT-qPCR) was performed to measure the mRNA expression of HIF-1α, TNF-α, VEGF and MMP-9; and Western blot (WB) was performed to determine the levels of proteins expressed in the EGFR-mediated PI3K/Akt and MAPK signaling pathways.
RESULTS: The results of the network pharmacology analysis showed that there were 35 active components in the frankincense and myrrh extracts targeting 151 key targets. The molecular docking analysis showed that both boswellic acid and stigmasterol showed strong affinity for the targets, with the greatest affinity for EGFR. Frankincense and myrrh treatment may play a role in the treatment of HCC by regulating hypoxia responses and vascular system-related pathological processes, such as cytokine-receptor binding, and pathways, such as those involving serine/threonine protein kinase complexes and MAPK, HIF-1 and ErbB signaling cascades. The animal experiment results were verified. First, we found that, through frankincense and/or myrrh treatment, the volume of subcutaneously transplanted HCC tumors was significantly reduced, and the pathological morphology was attenuated. Then, IF and TEM showed that frankincense and/or myrrh treatment reduced CD31 and collagen IV expression, increased the coverage of perivascular cells, tightened the connection between cells, and improved the shape of blood vessels. In addition, ELISA, RT-qPCR and WB analyses showed that frankincense and/or myrrh treatment inhibited the levels of hypoxia-inducible factors, inflammatory factors and angiogenesis-related factors, namely, HIF-1α, TNF-α, VEGF and MMP-9. Furthermore, mechanistic experiments illustrated that the effect of frankincense plus myrrh treatment was similar to that of an EGFR inhibitor with regard to controlling EGFR activation, thereby inhibiting the phosphorylation activity of its downstream targets: the PI3K/Akt and MAPK (ERK, p38 and JNK) pathways.
CONCLUSION: In summary, frankincense and myrrh treatment targets tumor blood vessels to exert anti-HCC effects EGFR-activated PI3K/Akt and MAPK signaling pathways, highlighting the potential of this dual TCM compound as an anti-HCC candidate.
World J Gastrointest Oncol. 2022 Feb;14(2):450-477.
PMID: 35317323 [PubMed - as supplied by publisher]
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| 26. |
Molecular evidences on anti-inflammatory, anticancer, and memory-boosting effects of frankincense.
Khajehdehi M, Khalaj-Kondori M, Baradaran B
Chemical diversity of natural products with drug-like features has attracted much attention from medicine to develop more safe and effective drugs. Their anti-inflammatory, antitumor, analgesic, and other therapeutic properties are sometimes more successful than chemical drugs in controlling disease due to fewer drug resistance and side effects and being more tolerable in a long time. Frankincense, the oleo gum resin extracted from the Boswellia species, contains some of these chemicals. The anti-inflammatory effect of its main ingredient, boswellic acid, has been traditionally used to treat many diseases, mainly those target memory functions. In this review, we have accumulated research evidence from the beneficial effect of Frankincense consumption in memory improvement and the prevention of inflammation and cancer. Besides, we have discussed the molecular pathways mediating the therapeutic effects of this natural supplement.
Phytother Res. 2022 Mar;36(3):1194-1215.
PMID: 35142408 [PubMed - indexed for MEDLINE]
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| 27. |
Review of the Chemical Composition, Pharmacological Effects, Pharmacokinetics, and Quality Control of .
Huang K, Chen Y, Liang K, Xu X, Jiang J, Liu M, Zhou F
OBJECTIVE: This review aimed to systematically summarize studies that investigated the bioactivities of compounds and extracts from Boswellia.
METHODS: A literature review on the pharmacological properties and phytochemicals of was performed. The information was retrieved from secondary databases such as PubMed, Chemical Abstracts Services (SciFinder), Google Scholar, and ScienceDirect.
RESULTS: The various extracts and compounds demonstrated pharmacological properties, such as anti-inflammatory, antitumour, and antioxidant activities. B. exhibited a positive effect on the treatment and prevention of many ageing diseases, such as diabetes, cancer, cardiovascular disease, and neurodegenerative diseases.
CONCLUSION: Here, we highlight the pharmacological properties and phytochemicals of and propose further evidence-based research on plant-derived remedies and compounds.
Evid Based Complement Alternat Med. 2022;2022():6627104.
PMID: 35069765 [PubMed - as supplied by publisher]
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| 28. |
Five terpenoids from the gum resin of Boswellia carterii and their cytotoxicity.
Feng Y, Zhang Q, Sun L
One undescribed tetracyclic triterpene (boswellicarin A), four undescribed pentacyclic triterpenes (boswellicarterins A-C) and one undescribed prenylaromadendrane-type diterpene (boscarterin A) were isolated from the gum resin of Boswellia carterii Birdw. (Burseraceae). Their structures were elucidated from NMR and HRESIMS spectroscopic data and ECD spectra. Boswellicarterins A-C and boscarterin A displayed weak and selective cytotoxicity against three human cancer cells (HepG2, A549 and MCF-7) by MTT assay.
Fitoterapia. 2021 Oct;154():105017.
PMID: 34418492 [PubMed - indexed for MEDLINE]
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| 29. |
Chloroform extract and acetyl-11-keto-beta-boswellic acid from Boswellia dalzielii stem bark induce apoptosis and cell cycle blockage in AW8507 cells.
Otitoju AP, Longdet IY, Alemika TE, Gota VP
BACKGROUND: Globally, head and neck cancer is the sixth most common cancer. Despite the advancement in treatment, drug resistance remains a major cause for setback. In an earlier work, the authors reported that Boswellia dalzielii (Hutch) stem bark exhibited dose-dependent cytotoxicity in head and neck cancer cells, AW8507. Therefore, the cell death induction effect of Boswellia dalzielii stem bark chloroform extract in head and neck cancer cell line, AW8507, and its derived constituent on cell cycle and apoptosis proteins was further investigated.
METHODS: The cell death induction activity of the Boswellia dalzielii stem bark chloroform fraction (CLBD) in AW8507 was determined using Annexin V-FITC/PI staining in flow cytometry. High-performance liquid chromatography-mass spectrometry was employed for compounds analysis of the CLBD, and reverse virtual screening was used to identify the mechanism of action of the compound, acetyl-11-keto-beta-boswellic acid, that was elucidated in the Boswellia dalzielii chloroform fraction.
RESULTS: The data obtained showed that Boswellia dalzielii stem bark Chloroform extract increased the percentage of cells presenting for early apoptosis from 4.14 to 10.10% in AW8507 cells. High-performance liquid chromatography-mass spectrometry analysis of the chloroform fraction identified acetyl-11-keto-beta-boswellic acid. Reverse virtual screening on selected proteins showed that acetyl-11-keto-beta-boswellic acid is a multi-protein target compound. It binds preferably to phosphorylated-cyclin dependent kinase 1 (p-CDK1) (binding score = - 9.2 kcal/mol), blocking the activation of cyclin B-CDK1 needed for cell cycle progression at G2/M phase of the cell cycle. Acetyl-11-keto-beta-boswellic acid also binds more tightly with αβ tubulin (binding score = 8.9 kcal/mol) than with the standard drug, docetaxel (binding score = 8.3 kcal/mol).
CONCLUSIONS: The results obtained confirmed the culpability of Boswellia dalzielii-derived acetyl-11-keto-beta-boswellic acid in the obstruction of the cell cycle progression in head and neck cancer cell line, AW8507; and the induction of apoptosis earlier reported for Boswellia dalzielii (Hutch) stem bark. Additional in vitro and/or in vivo studies would be required to validate in silico observations.
J Egypt Natl Canc Inst. 2021 Aug;33(1):20.
PMID: 34368899 [PubMed - indexed for MEDLINE]
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| 30. |
An engineered microfluidic blood-brain barrier model to evaluate the anti-metastatic activity of β-boswellic acid.
Vakilian S, Alam K, Al-Kindi J, Jamshidi-Adegani F, Rehman NU, Tavakoli R, Al-Riyami K, Hasan A, Zadjali F, Csuk R, Al-Harrasi A, Al-Hashmi S
BACKGROUND: The development of anti-cancer drugs with the ability to inhibit brain metastasis through the blood-brain barrier (BBB) is substantially limited due to the lack of reliable in vitro models.
MAIN METHODS: In this study, the Geltrex-based Transwell and microfluidic BBB models were applied to screen the effect of β-boswellic acid (β-BA) on the metastasis of MDA-MB-231 cells through the BBB in static and dynamic conditions, respectively.
MAJOR RESULTS: The toxicity assay revealed that β-BA deteriorates MDA-MB-231 cells, while β-BA had no detectable toxic effects on human umbilical vein endothelial cells (HUVECs) and astrocytes. Trans-endothelial electrical resistance evaluation showed sustainable barrier integrity upon treatment with β-BA. Vimentin expression in HUVECs, evaluated using western blot, confirmed superior barrier integrity in the presence of β-BA. The obtained results were confirmed using an invasion study with a cell tracker and a scanning electron microscope. β-BA significantly inhibited metastasis by 85%, while cisplatin (Cis), a positive control, inhibited cancer cell migration by 12% under static conditions. Upon applying a dynamic BBB model, it was revealed that β-BA-mediated metastasis inhibition was significantly higher than that mediated by Cis.
CONCLUSIONS AND IMPLICATIONS: In summary, the current study proved the anti-metastatic potential of β-BA in both static and dynamic BBB models.
Biotechnol J. 2021 Oct;16(10):e2100044.
PMID: 34313388 [PubMed - indexed for MEDLINE]
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| 31. |
Prenylaromadendrane-type diterpenoids from the gum resin of flueck and their cytotoxic effects.
Wang JJ, Suo XY, Sun HR, Wang X, Lin MB, Wang JH, Jiang JD, Ji TF
Two new prenylaromadendrane-type diterpenoids, and three known analogues, were isolated from the ethanol extract of the gum resin of Flueck. The structures of the new compounds were elucidated using 1 D and 2 D NMR spectroscopic analyses, mass spectrometric data, circular dichroism spectra, and comparison with the other compounds in the literature. One diterpenoid represents the first example of an acetoxyl-substituted prenylaromadendranoid in frankincense. All compounds exhibited notable cytotoxicity against human malignant glioma (U87-MG) cell line, with inhibitory rates exceeding that of the positive control 5-fluorouracil. However, nitric oxide inhibition induced by lipopolysaccarides was not observed in primary mouse peritoneal macrophages.
Nat Prod Res. 2022 Nov;36(21):5400-5406.
PMID: 34121549 [PubMed - indexed for MEDLINE]
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| 32. |
Molecular insight into isoform specific inhibition of PI3K-α and PKC-η with dietary agents through an ensemble pharmacophore and docking studies.
Bhaskar BV, Rammohan A, Babu TM, Zheng GY, Chen W, Rajendra W, Zyryanov GV, Gu W
Dietary compounds play an important role in the prevention and treatment of many cancers, although their specific molecular mechanism is not yet known. In the present study, thirty dietary agents were analyzed on nine drug targets through in silico studies. However, nine dietary scaffolds, such as silibinin, flavopiridol, oleandrin, ursolic acid, α-boswellic acid, β-boswellic acid, triterpenoid, guggulsterone, and oleanolic acid potentially bound to the cavity of PI3K-α, PKC-η, H-Ras, and Ras with the highest binding energy. Particularly, the compounds silibinin and flavopiridol have been shown to have broad spectrum anticancer activity. Interestingly, flavopiridol was embedded in the pockets of PI3K-α and PKC-η as bound crystal inhibitors in two different conformations and showed significant interactions with ATP binding pocket residues. However, complex-based pharmacophore modeling achieved two vital pharmacophoric features namely, two H-bond acceptors for PI3K-α, while three are hydrophobic, one cat-donor and one H-bond donor and acceptor for PKC-η, respectively. The database screening with the ChemBridge core library explored potential hits on a valid pharmacophore query. Therefore, to optimize perspective lead compounds from the hits, which were subjected to various constraints such as docking, MM/GBVI, Lipinski rule of five, ADMET and toxicity properties. Henceforth, the top ligands were sorted out and examined for vital interactions with key residues, arguably the top three promising lead compounds for PI3K-α, while seven for PKC-η, exhibiting binding energy from - 11.5 to - 8.5 kcal mol. Therefore, these scaffolds could be helpful in the development of novel class of effective anticancer agents.
Sci Rep. 2021 Jun;11(1):12150.
PMID: 34108504 [PubMed - indexed for MEDLINE]
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| 33. |
[One new cembranoid diterpene from gum resin of Boswellia carterii].
Xia H, Wang CC, Wang RY, Liang NY, Wang XY, Song YL, Zhao YF, Huo HX, Li J
This study aims to study the chemical components from the gum resin of Boswellia carterii. Five cembranoid diterpenes were isolated from the gum resin of B. carterii by various of column chromatographies including silica gel, Sephadex LH-20, and semi-preparative HPLC. Their structures were identified on the basis of physicochemical properties, mass spectrometry(MS), nuclear magnetic resonance(NMR), Ultraviolet(UV) and infrared(IR) spectroscopic data. These compounds were identified as(1S,2E,4R,5S,7E,11E)-4-methoxy-5-hydroxycembrane(1),(1R~*,4R~*,5E,8E,12E,15E)-4-hydroxycembra-5,8,12,15-tetraene(2), cembrene A(3),(3S,4S,7R)-4-hydroxycembrane(4), and pavidolide D(5). Compound 1 was a new compound. Compounds 2, 4, and 5 were obtained from the gum resin of B. carterii for the first time. Compound 2 showed weak inhibition on the human liver cancer cell line HepG2.
Zhongguo Zhong Yao Za Zhi. 2021 May;46(9):2215-2219.
PMID: 34047123 [PubMed - indexed for MEDLINE]
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| 34. |
Ameliorative Effects of Boswellic Acid on Fipronil-Induced Toxicity: Antioxidant State, Apoptotic Markers, and Testicular Steroidogenic Expression in Male Rats.
Tohamy HG, El-Kazaz SE, Alotaibi SS, Ibrahiem HS, Shukry M, Dawood MAO
The study investigated the ability of boswellic acid (BA) to alleviate the testicular and oxidative injury FPN insecticide intoxication in the male rat model. Rats were randomly assigned to six equivalent groups (six rats each) as the following: control rats orally administered with 2 mL physiological saline/kg of body weight (bwt); boswellic acid (BA1) rats orally administered 250 mg BA/kg bwt; boswellic acid (BA2) rats orally administered 500 mg BA/kg bwt; fipronil (FPN) rats orally administered 20 mg FPN/kg bwt; (FPN + BA1) rats orally administered 20 mg FPN/kg bwt plus 250 mg BA/kg bwt, and (FPN + BA2) rats orally administered 20 mg FPN/kg bwt plus 500 mg BA/kg bwt. After 60 days, semen viability percentage and live spermatozoa percentage were decreased, and a considerably increased abnormality of the sperm cells in FPN-administered rats improved substantially with the co-administration of BA. BA had refinement of the histological architecture of testes and sexual glands. Quantitative analysis recorded a noticeable decline in the nuclear cell-proliferating antigen (PCNA) percentage area. FPN triggered cell damage, which was suggested by elevated malondialdehyde and interleukin 6, tumor necrosis factors alpha, and decreased glutathione level. Proapoptotic factor overexpression is mediated by FPN administration, while it decreased the antiapoptotic protein expression. Similarly, BA has shown significant upregulation in steroidogenic and fertility-related gene expression concerning the FPN group. Pathophysiological damages induced by FPN could be alleviated by BA's antioxidant ability and antiapoptotic factor alongside the upregulation of steroidogenic and fertility-related genes and regimented the detrimental effects of FPN on antioxidant and pro-inflammatory biomarkers.
Animals (Basel). 2021 Apr;11(5):.
PMID: 33946602 [PubMed - as supplied by publisher]
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| 35. |
Complementary and alternative medicine in children with diffuse intrinsic pontine glioma-A SIOPE DIPG Network and Registry study.
El-Khouly FE, Adil SM, Wiese M, Hulleman E, Hendrikse NH, Kaspers GJL, Kramm CM, Veldhuijzen van Zanten SEM, van Vuurden DG,
INTRODUCTION: Diffuse intrinsic pontine glioma (DIPG) is a rare and aggressive childhood brainstem malignancy with a 2-year survival rate of <10%. This international survey study aims to evaluate the use of complementary and alternative medicine (CAM) in this patient population.
METHODS: Parents and physicians of patients with DIPG were asked to participate in a retrospective online survey regarding CAM use during time of illness.
RESULTS: Between January and May 2020, 120 parents and 75 physicians contributed to the online survey. Most physicians estimated that <50% of their patients used CAM, whereas 69% of the parents reported using CAM to treat their child during time of illness. Cannabis was the most frequently used form of CAM, followed by vitamins and minerals, melatonin, curcumin, and boswellic acid. CAM was mainly used with the intention of direct antitumor effect. Other motivations were to treat side effects of chemotherapy or to increase comfort of the child. Children diagnosed from 2016 onwards were more likely to use CAM (χ = 6.08, p = .014). No significant difference was found between CAM users and nonusers based on ethnicity (χ = 4.18, p = .382) or country of residence (χ = 9.37, p = .154). Almost 50% of the physicians do not frequently ask their patients about possible CAM use.
CONCLUSION: This survey demonstrates that worldwide, a considerable number of patients with DIPG use CAM. Physicians should be more aware of potential CAM use and actively discuss the topic. In addition, more research is needed to gain knowledge about possible anticancer effects of CAM and (positive/negative) interactions with conventional therapies.
Pediatr Blood Cancer. 2021 Sep;68(9):e29061.
PMID: 33942498 [PubMed - indexed for MEDLINE]
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| 36. |
A protein-sulfosalicylic acid/boswellic acids @metal-organic framework nanocomposite as anticancer drug delivery system.
Özsoy M, Atiroğlu V, Guney Eskiler G, Atiroğlu A, Deveci Ozkan A, Özacar M
The metal-organic frameworks (MOF) have shown fascinating possibilities in biomedical applications, designing a multifunctional drug delivery system based on the MOF is important. In this study, 5-sulfosalicylic acid and boswellic acids (BAs) were loaded to the pH sensitive zeolitic imidazolate framework-8 (ZIF-8) nanocomposite containing bovine serum albumin (BSA) as the center. The ZIF layer acts as a capsule for the nontoxic storage of 5-sulfosalicylic acid and boswellic acids (BAs) under physiological conditions. The results of the characterization demonstrated the performance of the nanocarrier formation. The pH-sensitive drug release of 5-sulfosalicylic acid was detected due to the innate pH-dependent stability of ZIF-8. An effective pH-sensitive drug delivery system using a 5-sulfosalicylic acid/BSA@ZIF-8, and 5-sulfosalicylic acid/BSA/BAs@ZIF-8, in which the 5-sulfosalicylicacid is not free in physiological pH but it is released at acidic pH (5.0) has been fabricated. The best biocompatibility has been found in 5-sulfosalicylic acid/BSA/BAs@ZIF-8 comparing to the 5-sulfosalicylic acid/BSA, 5-sulfosalicylic acid /BSA/BAs, and 5-sulfosalicylic acid/BSA@ZIF-8. Additionally, 5-sulfosalicylic acid/BSA /BAs@ZIF-8 exhibited higher effectiveness than other compounds against the breast cancer cell line, MCF-7, with less toxicity. It is concluded from the results of the current study that the fabricated ZIF-8 based nanocarrier may potentially provide therapeutic effects on breast cancer cells.
Colloids Surf B Biointerfaces. 2021 Aug;204():111788.
PMID: 33932885 [PubMed - indexed for MEDLINE]
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| 37. |
Mechanisms exploration of Xiaojin Pills on lung cancer based on metabolomics and network pharmacology.
Cao B, Lin J, Wu Z, Liu H, Zhang D, Xu H, Xu R, Han L
OBJECTIVES: This study was designed to evaluate the pharmacological activity and therapeutic mechanism of Xiaojin Pills (XJW) on lung cancer.
METHODS: Mice were orally administered with Xiaojin Pills for 21 days. Tumour samples were collected to evaluate the antilung cancer effect, and blood samples were collected to identify differential metabolites with metabolomics. Through the analysis of network pharmacology, the active ingredients and targets related to XJW therapy for lung cancer were filtered.
KEY FINDINGS: Different expression of seven metabolites related to seven pathways, including Arachidonic acid metabolism, Citrate cycle, tryptophan metabolism, glyoxylate and dicarboxylate metabolism, arginine and proline metabolism, primary bile acid biosynthesis and nicotinate and nicotinamide metabolism, were demonstrated to explain the efficacy of XJW in the treatment of lung cancer. Furthermore, a total of 19 active ingredients (ursolic acid, α-thujone, pelargonidin, succinic acid, boswellic acid, muscone, daidzein, xanthorrhizol, isoeugenol, oleic acid, β-caryophyllene, vanillin, β-sitosterol, lupeol, palmitic acid, eugenol, methylbutenol, β-elemene and quercetin) acted directly on 9 targets (CAT, PTGS2, PTGS1, CTH, ABTA, ALT1, ME2, AGXT and AGXT 2) and regulated 3 out of 7 metabolites (3-Hydroxyanthranilic acid, Pyruvate and Prostaglandin G2).
CONCLUSIONS: Through metabolomics and network pharmacology analyses, this study demonstrated that the major metabolites of XJW in treating lung cancer were regulated by multitarget and multicomponent interaction network.
J Pharm Pharmacol. 2021 Jul;73(8):1071-1079.
PMID: 33864464 [PubMed - indexed for MEDLINE]
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| 38. |
Boswellic acid exerts potent anticancer effects in HCT-116 human colon cancer cells mediated via the induction of apoptosis, cell cycle arrest, cell migration inhibition and inhibition of PI3K/AKT signalling pathway.
Wang D, Song SGJBY
The Editors of JBUON issue an Expression of Concern to 'Boswellic acid exerts potent anticancer effects in HCT-116 human colon cancer cells mediated via induction of apoptosis, cell cycle arrest, cell migration inhibition and inhibition of PI3K/AKT signalling pathway', by Dan Wang, Shuke Ge, Jichang Bai, Yongwei Song, JBUON 2018;23(2):340-345; PMID:29745074. Following the publication of the above article, readers drew to our attention that part of the data was possibly unreliable. We sent emails to the authors with a request to provide the raw data to prove the originality, but received no reply. Therefore, as we continue to work through the issues raised, we advise readers to interpret the information presented in the article with due caution. We thank the readers for bringing this matter to our attention. We apologize for any inconvenience it may cause.
J BUON. 2021;26(1):293.
PMID: 33721478 [PubMed - indexed for MEDLINE]
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| 39. |
Boswellic acids: privileged structures to develop lead compounds for anticancer drug discovery.
Hussain H, Ali I, Wang D, Hakkim FL, Westermann B, Rashan L, Ahmed I, Green IR
: Cancer has been identified to be the second major cause of death internationally as exemplified by ca. 9.6 million deaths in 2018 along with ca. 18 million new patients in 2018 that have been recorded. Natural boswellic acids (BAs) and their source, frankincense, have been reported to possess and anticancer effects toward various cancer cells.: This comprehensive review focuses on the importance of boswellic acids (BAs) for the establishment of future treatments of cancer. Moreover, potent semisynthetic derivatives of BAs have been described along with their mode of action. In addition, important structural features of the semisynthetic BAs required for cytotoxic effects are also discussed.: Numerous semisynthetic BAs illustrate excellent cytotoxic effects. Of note, compounds bearing cyanoenone moieties in ring A, endoperoxides and hybrids display increased and more potent cytotoxic effects compared with other semisynthetic BAs. Moreover, BAs have the potential to conjugate or couple with other anticancer compounds to synergistically increase their combined anticancer effects. In addition, to get derived BAs to become lead anticancer compounds, future research should focus on the preparation of ring A cyanoenones, endoperoxides, and C-24 amide analogs.
Expert Opin Drug Discov. 2021 Aug;16(8):851-867.
PMID: 33650441 [PubMed - indexed for MEDLINE]
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| 40. |
Role of Testosterone Levels on the Combinatorial Effect of Extract and Enzalutamide on Androgen Dependent LNCaP Cells and in Patient Derived Cells.
Pillai P, Pooleri GK, Nair SV
Co-therapy with herbal extracts along with current clinical drugs is being increasingly recognized as a useful complementary treatment for cancer. The anti-cancer property of the phyto-derivative acetyl-11 keto β boswellic acid (AKBA) has been studied in many cancers, including prostate cancer. However, the whole extract of the gum resin (BS) and anti-androgen enzalutamide has not been explored in prostate cancer to date. We hypothesized that the BS extract containing 30% (AKBA) with enzalutamide acted synergistically in the early phase of cancer, especially in LNCaP cells, by inhibiting androgen receptor (AR) and by reducing cell proliferation, and further, that the extract would be superior to the action of the active ingredient AKBA when used alone or in combination with enzalutamide. To test our hypothesis, we treated LNCaP cells with BS extract or AKBA and enzalutamide both individually and in combination to analyze cell viability under different levels of dihydrotestosterone (DHT). The inhibition of androgen receptor (AR) followed by the expression of prostate-specific antigen (PSA) and the efflux mechanism of the cells were analyzed to determine the effect of the combination on the cellular mechanism. Cells derived from prostate cancer patients were also tested with the combination. Only 6 µM enzalutamide along with BS in the range of 4.1 µg/ml to 16.4 µg/ml gave the best synergistic results with nearly 50% cell killing even though standard enzalutamide doses were as high as 48 µM. Cell killing was most effective at intermediate DHT concentrations of approximately 1 nM, which corresponds to normal physiological serum levels of DHT. The Pgp expression level and the androgen receptor expression levels were reduced under the combination treatment; the former helping to minimize drug efflux and the latter by reducing the sensitivity to hormonal changes. Furthermore, the combination reduced the PSA level secreted by the cells. In contrast, AKBA could not achieve the needed synergism for adequate cell killing at equivalent concentrations. The combination of enzalutamide and BS extract containing 30% AKBA because of their synergistic interaction is an attractive therapeutic option for treating early stage (hormone-dependent) prostate cancer and is superior to the use of AKBA alone.
Integr Cancer Ther. 2021;20():1534735421996824.
PMID: 33615860 [PubMed - indexed for MEDLINE]
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| 41. |
Simultaneous determination of five bioactive components of XiaoJin Capsule in normal and mammary gland hyperplasia rat plasma using LC-MS/MS and its application to a pharmacokinetic study.
Wang X, Lei H, Qi X, Guo X, Xu X, Zu X, Ye J
XiaoJin Capsule (XJC) is a classic Traditional Chinese Medicine formula for clinical treatment of thyroid nodules, mammary gland hyperplasia and breast cancer. For the specification and rational application of XJC in the future, an accurate and specific LC-MS/MS method was developed and validated for quantitative determination of five components in rat plasma after oral administration of XJC. The collected plasma samples were extracted by protein precipitation with methanol-acetonitrile (1:3, v/v) mixture solvent and separated on a C column using a gradient elution system. Mass spectrometry was performed on a triple quadrupole mass spectrometer, and samples were detected in positive ionization and multiple reactions monitoring mode. The method was properly validated in terms of linearity, precision, accuracy, recovery, matrix effect and stability. All calibration curves showed good linearity (r > 0.9910) over their concentration ranges. The intra- and inter-day precisions (RSD) were within 11.0%, and the LLOQ was 0.1, 0.2, 0.5, 7.5 and 7.5 ng/ml for aconine, songorine, neoline, 3-acetyl-11-keto-β-boswellic acid and 11-keto-β-boswellic acid, respectively. Extraction recovery, matrix effect and stability were satisfactory in rat plasma. This established method was successfully applied to a pharmacokinetics study of five compounds after oral administration of XJC to normal and mammary gland hyperplasia model rats.
Biomed Chromatogr. 2021 Mar;35(3):e5000.
PMID: 33460195 [PubMed - indexed for MEDLINE]
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| 42. |
11-Keto-α-Boswellic Acid, a Novel Triterpenoid from spp. with Chemotaxonomic Potential and Antitumor Activity against Triple-Negative Breast Cancer Cells.
Schmiech M, Ulrich J, Lang SJ, Büchele B, Paetz C, St-Gelais A, Syrovets T, Simmet T
Boswellic acids, and particularly 11-keto-boswellic acids, triterpenoids derived from the genus (), are known for their anti-inflammatory and potential antitumor efficacy. Although boswellic acids generally occur as α-isomers (oleanane type) and β-isomers (ursane type), 11-keto-boswellic acid (KBA) was found only as the β-isomer, β-KBA. Here, the existence and natural occurrence of the respective α-isomer, 11-keto-α-boswellic acid (α-KBA), is demonstrated for the first time. Initially, α-KBA was synthesized and characterized by high-resolution mass spectrometry (HR-MS) and nuclear magnetic resonance (NMR) spectroscopy, and a highly selective, sensitive, and accurate high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS) method was developed by Design of Experiments (DoE) using a pentafluorophenyl stationary phase. This method allowed the selective quantification of individual 11-keto-boswellic acids and provided evidence for α-KBA in spp. oleogum resins. The contents of α-KBA as well as further boswellic acids and the composition of essential oils were used to chemotaxonomically classify 41 oleogum resins from 9 different species. Moreover, α-KBA exhibited cytotoxicity against three treatment-resistant triple-negative breast cancer (TNBC) cell lines in vitro and also induced apoptosis in MDA-MB-231 xenografts in vivo. The respective β-isomer and the acetylated form demonstrate higher cytotoxic efficacies against TNBC cells. This provides further insights into the structure-activity relationship of boswellic acids and could support future developments of potential anti-inflammatory and antitumor drugs.
Molecules. 2021 Jan;26(2):.
PMID: 33445710 [PubMed - indexed for MEDLINE]
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| 43. |
Phyto-Facilitated Bimetallic ZnFeO Nanoparticles via Boswellia carteri: Synthesis, Characterization, and Anti-Cancer Activity.
Imraish A, Al-Hunaiti A, Abu-Thiab T, Ibrahim AA, Hwaitat E, Omar A
BACKGROUND: The growing dissatisfaction with the available traditional chemotherapeutic agents has enhanced the need to develop new methods for obtaining materials with more effective and safe anti-cancer properties. Over the past few years, the usage of metallic nanoparticles has been a target for researchers of different scientific and commercial fields due to their tiny sizes, environment-friendly properties, and a wide range of applications. To overcome the obstacles of traditional physical and chemical methods for the synthesis of such nanoparticles, a new, less expensive, and eco-friendly method has been adopted using natural existing organisms as a reducing agent to mediate the synthesis of the desired metallic nanoparticles from their precursors, a process called green biosynthesis of nanoparticles.
OBJECTIVE: In the present study, zinc-iron bimetallic nanoparticles (ZnFeO) were synthesized via an aqueous extract of Boswellia carteri resin mixed with zinc acetate and iron chloride precursors, and they were tested for their anticancer activity.
METHODS: Various analytic methods were applied for the characterization of the phyto synthesized ZnFeO, and they were tested for their anticancer activity against MDA-MB-231, K562, MCF-7 cancer cell lines, and normal fibroblasts.
RESULTS: Our results demonstrate the synthesis of cubic structured bimetallic nanoparticles ZnFeO with an average diameter of 10.54 nm. MTT cytotoxicity assay demonstrates that our phyto-synthesized ZnFeO nanoparticles exhibited a selective and potent anticancer activity against K562 and MDA-MB-231 cell lines with IC50 values 4.53 μM and 4.19 μM, respectively.
CONCLUSION: In conclusion, our biosynthesized ZnFeO nanoparticles show a promising, environmentally friendly, and low coast chemotherapeutic approach against selective cancers with a predicted low adverse side effect toward normal cells. Further, in vivo, advanced animal research should be done to execute their applicability in living organisms.
Anticancer Agents Med Chem. 2021;21(13):1767-1772.
PMID: 33342418 [PubMed - indexed for MEDLINE]
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| 44. |
Acetyl-11-keto-β-boswellic acid inhibits proliferation and induces apoptosis of gastric cancer cells through the phosphatase and tensin homolog /Akt/ cyclooxygenase-2 signaling pathway.
Sun MX, He XP, Huang PY, Qi Q, Sun WH, Liu GS, Hua J
BACKGROUND: Gastric cancer is one of the most common malignant tumors of the digestive system worldwide, posing a serious danger to human health. Cyclooxygenase (COX)-2 plays an important role in the carcinogenesis and progression of gastric cancer. Acetyl-11-keto-β-boswellic acid (AKBA) is a promising drug for cancer therapy, but its effects and mechanism of action on human gastric cancer remain unclear.
AIM: To evaluate whether the phosphatase and tensin homolog (PTEN)/Akt/COX-2 signaling pathway is involved in the anti-tumor effect of AKBA in gastric cancer.
METHODS: Human poorly differentiated BGC823 and moderately differentiated SGC7901 gastric cancer cells were routinely cultured in Roswell Park Memorial Institute 1640 medium supplemented with 10% fetal bovine serum and 1% penicillin/streptomycin. Gastric cancer cell proliferation was determined by methyl thiazolyl tetrazolium colorimetric assay. Apoptosis was measured by flow cytometry. Cell migration was assessed using the wound-healing assay. Expression of Bcl-2, Bax, proliferating cell nuclear antigen, PTEN, p-Akt, and COX-2 were detected by Western blot analysis. A xenograft nude mouse model of human gastric cancer was established to evaluate the anti-cancer effect of AKBA .
RESULTS: AKBA significantly inhibited the proliferation of gastric cancer cells in a dose- and time-dependent manner, inhibited migration in a time-dependent manner, and induced apoptosis in a dose-dependent manner ; it also inhibited tumor growth . AKBA up-regulated the expression of PTEN and Bax, and down-regulated the expression of proliferating cell nuclear antigen, Bcl-2, p-Akt, and COX-2 in a dose-dependent manner. The PTEN inhibitor bpv (Hopic) reversed the high expression of PTEN and low expression of p-Akt and COX-2 that were induced by AKBA. The Akt inhibitor MK2206 combined with AKBA down- regulated the expression of p-Akt and COX-2, and the combined effect was better than that of AKBA alone.
CONCLUSION: AKBA inhibits the proliferation and migration and promotes the apoptosis of gastric cancer cells through the PTEN/Akt/COX-2 signaling pathway.
World J Gastroenterol. 2020 Oct;26(38):5822-5835.
PMID: 33132637 [PubMed - indexed for MEDLINE]
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| 45. |
Antiproliferative effects of boswellic acid-loaded chitosan nanoparticles on human lung cancer cell line A549.
Solanki N, Mehta M, Chellappan DK, Gupta G, Hansbro NG, Tambuwala MM, Aa Aljabali A, Paudel KR, Liu G, Satija S, Hansbro PM, Dua K, Dureja H
In the present study boswellic acids-loaded chitosan nanoparticles were synthesized using ionic gelation technique. The influence of independent variables were studied and optimized on dependent variables using central composite design. The designed nanoparticles were observed spherical in shape with an average size of 67.5-187.2 nm and have also shown an excellent entrapment efficiency (80.06 ± 0.48). The cytotoxicity assay revealed enhanced cytotoxicity for drug-loaded nanoparticles in contrast to the free drug having an IC value of 17.29 and 29.59 μM, respectively. Flow cytometry confirmed that treatment of cells with 40 μg/ml had arrested 22.75 ± 0.3% at SubG phase of the cell cycle when compared with untreated A459 cells. The observed results justified the boswellic acids-loaded chitosan nanoparticles were effective due to greater cellular uptake, sustained intercellular drug retention and enhanced antiproliferative effect by inducing apoptosis.
Future Med Chem. 2020 Nov;12(22):2019-2034.
PMID: 33124483 [PubMed - indexed for MEDLINE]
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| 46. |
-Mediated Silver Nanoparticles Inhibited Acute Myeloid Leukemia (AML) Kasumi-1 Cells by Inducing Cell Cycle Arrest.
Adebayo IA, Usman AI, Shittu FB, Ismail NZ, Arsad H, Muftaudeen TK, Samian MR
BACKGROUND: Acute myeloid leukemia (AML) persists to be a major health problem especially among children as effective chemotherapy to combat the disease is yet to be available. is a well-known herb that is traditionally used for treatment and management of many diseases including degenerative diseases. In this study, silver nanoparticles were synthesized from the phytochemicals of stem bark aqueous extract. The silver nanoparticles were characterized by carrying out Fourier Transform Infrared (FTIR) spectroscopy, Energy Filtered Scanning Electron Microscopy (FESEM), X-ray diffraction, and Dynamic Light Scattering (DLS) analyses. Antioxidant capacity of the nanoparticles was evaluated using 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay, and the antiproliferative effect of the nanoparticles on Kasumi-1 leukemia cells was investigated using PrestoBlue assay. Flow cytometry analysis was performed to observe the effect of the nanoparticles on the leukemia cell cycle progression.
RESULTS: Our findings revealed that the synthesized silver nanoparticles were formed from electrons of the plant phytochemicals which include aromatic compounds, ethers, and alkynes. FESEM analysis revealed that the sizes of the nanoparticles range from 12 nm to 101 nm; however, DLS analysis estimated a larger average size of the nanoparticles (108.3 nm) because it measured the hydrodynamic radii of the nanoparticles. The zeta potential of the nanoparticles was -16 nm, and the XRD pattern of the nanoparticles has distinct peaks at 38.02°, 42.94°, 64.45°, 77.20°, and 81.47°, which is typical of face-centered cubic (fcc) structure of silver. The Trolox Equivalence Antioxidant Capacity (TEAC) of the nanoparticles was estimated to be 300.91 M Trolox/mg silver nanoparticles. The nanoparticles inhibited Kasumi-1 cell proliferation. The half minimal inhibitory concentrations (IC50s) that inhibited Kasumi-1 cell proliferation are 49.5 g/ml and 13.25 g/ml at 48 and 72 hours, respectively. The nanoparticles induced cell cycle arrest in the Kasumi-1 cells at S (5% increase) and G2/M (3% increase) phases.
CONCLUSION: The nanoparticles synthesized from the stem bark extract of inhibit the growth of Kasumi-1 leukemia cells by activating cell cycle arrest; thus, they are potential antileukemic agents.
Bioinorg Chem Appl. 2020;2020():8898360.
PMID: 33029114 [PubMed - as supplied by publisher]
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| 47. |
Boswellic acid sensitizes gastric cancer cells to Cisplatin-induced apoptosis via p53-mediated pathway.
Al-Bahlani S, Burney IA, Al-Dhahli B, Al-Kharusi S, Al-Kharousi F, Al-Kalbani A, Ahmed I
BACKGROUND: Cisplatin (CDDP) is an effective anticancer drug for Gastric cancer (GC) that induces apoptosis by altering pro- (p53) and anti-apoptotic (Akt and NFkB) proteins; however, chemoresistance remains a big challenge. Additional compounds with promising anticancer effects such as AKBA (Acetyl-keto-beta boswellic acid) may overcome the resistance. However, its role in CDDP-induced apoptosis in GC has not been studied. This study aimed to examine the effectiveness of AKBA on p53-mediated, CDDP-induced apoptosis in GC cells. AGS and NCI-N87 cells were treated with different concentrations (0, 25, 50, 100 μM) of CDDP and/or AKBA.
METHODS: P53, Akt and NFkB proteins and apoptosis were assessed by Western blot and flow cytometry. The role of p53 was determined by inhibiting its function via the siRNA approach.
RESULTS: The results revealed that CDDP and AKBA significantly increased p53 content in both cells, while Akt and NFkB were significantly decreased. Both compounds significantly induced apoptosis in a dose-dependent manner. AKBA sensitized GC cells to CDDP-induced apoptosis by altering the protein expression. P53 downregulation affected Akt and NFkB proteins with a slight increase in apoptosis induction in the combination treated groups.
CONCLUSIONS: Altogether, our findings suggest that AKBA enhances GC cell sensitivity to CDDP-induced apoptosis via the p53 pathway.
BMC Pharmacol Toxicol. 2020 Sep;21(1):64.
PMID: 32867831 [PubMed - indexed for MEDLINE]
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| 48. |
Exploring the Regulation Mechanism of Xihuang Pill, and β-Boswellic Acid on the Biomolecular Network of Triple-Negative Breast Cancer Based on Transcriptomics and Chemical Informatics Methodology.
Yang K, Zeng L, Ge A, Bao T, Xu T, Xie X, Liu L
BACKGROUND: Xihuang Pill (XHP) is mainly used to treat "Ru Yan (breast cancer)". Evidence-based medical evidence and showed that XHP improves the efficacy of chemotherapy and reduced chemotherapy-induced toxicity in breast cancer patients. However, the mechanism of XHP against breast cancer is not clear.
METHODS: The effect of XHP extract on cell half-inhibitory concentration (IC50) and cell viability of MD-MB-231 cells was detected by CCK-8 method. The cell inhibition rate of MDA-MB-453 cells were detected by MTT method. Apoptosis was detected by flow cytometry, cell transfer ability was detected by Transwell method, and cell proliferation ability was detected by colony formation assay. The expression of Notch1, β-catenin and c-myc mRNA in MDA-MB-453 cells were detected by real-time fluorescence quantitative PCR. Then, chemical informatics and transcriptomics methodology was utilized to predict the potential compounds and targets of XHP, and collect triple negative breast cancer (TNBC) genes and the data of and β-boswellic acid intervention MD-MB-231 cells (from GSE102891). The cytoscape software was utilized to undergo network construction and network analysis. Finally, the data from the network analysis was imported into the DAVID database for enrichment analysis of signaling pathways and biological processes.
RESULTS: The IC50 was 15.08 g/L (for MD-MB-231 cells). After interfering with MD-MB-231 cells with 15.08 g/L XHP extract for 72 h, compared with the control group, the cell viability, migration and proliferation was significantly decreased, while early apoptosis and late apoptosis were significantly increased (P < 0.01). After interfering with MDA-MB-453 cells with 6 g/L XHP extract for 72 h, compared with the control group, the cell inhibition and apoptosis rate increased, while the expression of Notch1, β-catenin and c-myc mRNA decreased. (P < 0.05). The chemical informatics and transcriptomics analysis showed that four networks were constructed and analyzed: (1) potential compounds-potential targets network of XHP; (2) XHP-TNBC PPI network; (3) DEGs PPI network of -treated MD-MB 231 cells; (4) DEGs PPI network of β-boswellic acid -treated MD-MB 231 cells. Several anti-TNBC biological processes, signaling pathways, targets and so on were obtained.
CONCLUSION: XHP may exert anti-TNBC effects through regulating biological processes, signaling pathways, targets found in this study.
Front Pharmacol. 2020;11():825.
PMID: 32595497 [PubMed - as supplied by publisher]
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| 49. |
Acetyl-11-keto-β-boswellic acid enhances the cisplatin sensitivity of non-small cell lung cancer cells through cell cycle arrest, apoptosis induction, and autophagy suppression via p21-dependent signaling pathway.
Lv M, Zhuang X, Zhang Q, Cheng Y, Wu D, Wang X, Qiao T
Cisplatin-based therapy is a widely used chemotherapeutic regimen for non-small cell lung cancer (NSCLC); however, drug resistance limits its efficacy. Acetyl-11-keto-β-boswellic acid (AKBA), a bioactive compound from frankincense, has been shown to exert anti-cancer effects. The aim of this study is to explore the potential of AKBA in combination with cisplatin as a new regimen for NSCLC. CCK8 assay and clone formation assay were used to determine the effects of AKBA in combination with cisplatin on cell viability of NSCLC cell lines. A three-dimensional spherification assay was used to simulate in vivo tumor formation. Flow cytometry was performed to examine cell cycle distribution and the percentages of apoptotic cells. The associated proteins and mRNA of cell cycle, apoptosis, and autophagy were measured by western blotting and real-time fluorescence quantitative PCR. Immunofluorescence assay was used to test apoptotic nuclei and autolysosome. Small interfering RNA experiments were used to silence the expression of p21. Combination treatment of AKBA and cisplatin inhibited cell viability, clone formation, and three-dimensional spherification, enhanced G/G phase arrest, increased the percentages of apoptotic cells, and decreased the ratio of positive autolysosomes, compared with cisplatin alone. AKBA in combination with cisplatin suppressed the protein expressions of cyclin A2, cyclin E1, p-cdc2, CDK4, Bcl-xl, Atg5, and LC3A/B, and upregulated p27 and p21 mRNA levels in A549 cells. Downregulation of p21 decreased G/G phase arrest and the percentages of apoptotic cells, and promoted autophagy in NSCLC A549 cells. Our study demonstrates that AKBA enhances the cisplatin sensitivity of NSCLC cells and that the mechanisms involve G/G phase arrest, apoptosis induction, and autophagy suppression via targeting p21-dependent signaling pathway.
Cell Biol Toxicol. 2021 Apr;37(2):209-228.
PMID: 32562082 [PubMed - indexed for MEDLINE]
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| 50. |
Silymarin, boswellic acid and curcumin enriched dietetic formulation reduces the growth of inherited intestinal polyps in an animal model.
Girardi B, Pricci M, Giorgio F, Piazzolla M, Iannone A, Losurdo G, Principi M, Barone M, Ierardi E, Di Leo A
BACKGROUND: Some substances of plant origin have been reported to exert an effect in reducing intestinal neoplasm development, especially in animal models. Adenomatous polyposis coli multiple intestinal neoplasia - Apc is the most studied murine model of genetic intestinal carcinogenesis.
AIM: To assess whether an enriched nutritional formulation (silymarin, boswellic acid and curcumin) with proven and anti-carcinogenetic properties may prevent inherited intestinal cancer in animal model.
METHODS: Forty adenomatous polyposis coli multiple intestinal neoplasia - Apc mice were used for the study of cancer prevention. They were divided into two groups: 20 assumed standard and 20 enriched diet. At the 110 d animals were sacrificed. In each group, four subgroups received intraperitoneal bromodeoxyuridine injection at different times (24, 48, 72 and 96 h before the sacrifice) in order to assess epithelial turnover. Moreover, we evaluated the following parameters: Intestinal polypoid lesion number and size on autoptic tissue, dysplasia and neoplasia areas by histological examination of the whole small intestine, inflammation by histology and cytokine mRNA expression by real-time polymerase chain reaction, bromodeoxyuridine and TUNEL immuno-fluorescence for epithelial turnover and apoptosis, respectively. Additionally, we performed western blotting analysis for the expression of estrogen alpha and beta receptors, cyclin D1 and cleaved caspase 3 in normal and polypoid tissues.
RESULTS: Compared to standard, enriched diet reduced the total number (203 416) and the mean ± SD/animal (12.6 ± 5.0 26.0 ± 8.8; < 0.001) of polypoid lesions. In enriched diet group a reduction in polyp size was observed ( < 0.001). Histological inflammation and pro-inflammatory cytokine expression were similar in both groups. Areas of low-grade dysplasia ( < 0.001) and intestinal carcinoma (IC; < 0.001) were significantly decreased in enriched diet group. IC was observed in 100% in standard and 85% in enriched formulation assuming animals. Enriched diet showed a faster epithelial migration and an increased apoptosis in normal mucosa and low-grade dysplasia areas ( < 0.001). At western blotting, estrogen receptor beta protein was well expressed in normal mucosa of enriched and standard groups, with a more marked trend associated to the first one. Estrogen receptor alpha was similarly expressed in normal and polypoid mucosa of standard and enriched diet group. Cleaved caspase 3 showed in normal mucosa a stronger signal in enriched than in standard diet. Cyclin D1 was more expressed in standard than enriched diet group of both normal and polypoid tissue.
CONCLUSION: Our results are suggestive of a chemo-preventive synergic effect of the components (silymarin, boswellic acid and curcumin) of an enriched formulation in inherited IC. This effect may be mediated by the reduction of epithelial proliferation, the increase of apoptosis and the acceleration of villous cell renewal due to dietary formulation intake.
World J Gastroenterol. 2020 Apr;26(14):1601-1612.
PMID: 32327909 [PubMed - indexed for MEDLINE]
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| 51. |
Frankincense and myrrh and their bioactive compounds ameliorate the multiple myeloma through regulation of metabolome profiling and JAK/STAT signaling pathway based on U266 cells.
Gao R, Miao X, Sun C, Su S, Zhu Y, Qian D, Ouyang Z, Duan J
BACKGROUND: Frankincense and myrrh are used as traditional anti-inflammatory and analgesic medicines in China. It has been reported that frankincense and myrrh have significant anti-tumor activities. The present study was designed to investigate the inhibitory efficacy of frankincense ethanol extracts (RXC), myrrh ethanol extracts (MYC), frankincense -myrrh ethanol extracts (YDC), frankincense -myrrh water extracts (YDS) and their main compounds on U266 human multiple myeloma cell line.
METHODS: The inhibition effects of cell proliferation was evaluated by MTT assays. Cell culture supernatant was collected for estimation of cytokines. Western blot analysis was designed to investigate the regulatory of JAK/STAT signal pathway. In addition, cell metabolomics based on the ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF-MS) had been established to investigate the holistic efficacy of frankincense and myrrh on U266 cells. Acquired data were processed by partial least-squares discriminant analysis (PLS-DA) and orthogonal projection to latent structures squares-discriminant analysis (OPLS-DA) to identify potential biomarkers.
RESULTS: RXC, MYC significantly inhibited the proliferation of U266 cells at dose of 25-400 μg/mL, YDC and YDS at the dose of 12.5-400 μg/mL. 3-O-acetyl-α-boswellic acid, 3-acetyl-11 keto-boswellic acid and 11-keto-boswellic acid had the most significant anti- multiple myeloma activities in the 10 compounds investigated, therefore these 3 compounds were selected as representatives for Elisa assay and western blotting experiments. All the extracts and active compounds ameliorated the secretion of cytokines and down-regulated the expression of JAK/STAT signaling pathway-related proteins. Comparing RXC, MYC, YDC and YDS-treated U266 cells with vehicle control (DMSO), 13, 8, 7, 7 distinct metabolites and 2, 2, 3, 0 metabolic target pathways involved in amino acid metabolism, lipid metabolism, vitamin metabolism, arachidonic acid were identified, respectively.
CONCLUSIONS: Taken together our results suggest that the frankincense and myrrh and their bioactive compounds inhibit proliferation of U266 multiple myeloma cells by regulating JAK/STAT signaling pathway and cellular metabolic profile.
BMC Complement Med Ther. 2020 Mar;20(1):96.
PMID: 32293402 [PubMed - indexed for MEDLINE]
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| 52. |
Acetyl-11-keto-β-boswellic Acid Inhibits Precancerous Breast Lesion MCF-10AT Cells via Regulation of LINC00707/miR-206 that Reduces Estrogen Receptor-α.
Jiang X, Liu Y, Zhang G, Lin S, Yuan N, Wu J, Yan X, Ma Y, Ma M
PURPOSE: Acetyl-11-keto-β-boswellic acid (AKBA) has therapeutic effects on a range of diseases, including tumours. lncRNAs, as competing endogenous RNAs (ceRNAs), can interact with miRNAs to regulate the expression of target genes, which can affect the development of tumors. Here, we examined the effects of AKBA on breast precancerous lesions MCF-10AT cells.
METHODS: The expression profiles of breast cancer (BC) tissue were collated from The Cancer Genome Atlas (TCGA), and the lncRNA-miRNA-mRNA ceRNA network was constructed. AKBA targets were predicted by network pharmacology. The expression of long intergenic nonprotein-coding RNA 707 (LINC00707), miR-206 and ER-α was determined by qRT-PCR. Cell viability, apoptosis and cycle were assessed by CCK-8 and flow cytometry. Protein levels were measured by Western blotting.
RESULTS: A total of 3205 differentially expressed mRNAs, 104 miRNAs, and 605 lncRNAs were identified. The ceRNA network consisting of 9 lncRNAs, 15 miRNAs and 82 mRNAs was constructed. We found that LINC00707 was up-regulated and miR-206 was down-regulated in MCF-10AT cells. Transfected si-LINC00707 could inhibit cell proliferation, induce cell apoptosis and cycle arrest of MCF-10AT cells. In addition, network pharmacology predicted that AKBA may regulate the ESR1 in the treatment of BC. Our research demonstrated that AKBA could induce cell apoptosis and G1-phase arrest and inhibit ER-α expression via LINC00707/miR-206 in MCF-10AT cells.
CONCLUSION: AKBA inhibited MCF-10AT cells via regulation of LINC00707/miR-206 that reduces ER-α.
Cancer Manag Res. 2020;12():2301-2314.
PMID: 32273767 [PubMed - as supplied by publisher]
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| 53. |
Acetyl-11-Keto-β-Boswellic Acid Exerts the Anti-Cancer Effects via Cell Cycle Arrest, Apoptosis Induction and Autophagy Suppression in Non-Small Cell Lung Cancer Cells.
Lv M, Shao S, Zhang Q, Zhuang X, Qiao T
OBJECTIVE: Acetyl-11-keto-β-boswellic acid (AKBA) is a triterpenoid, which is the main component of boswellic acid from Boswellia Serrata, a medicinal plant that has shown immense potential in anti-cancer therapy. This study aims to explore the roles and molecular mechanisms of AKBA on cell behavior in non-small cell lung cancer (NSCLC) cells.
MATERIALS AND METHODS: The effects of AKBA on the cell viability in A549, H460, H1299, and BEAS-2B cells were determined by the CCK-8 assay. The colony formation assay was used to identify the effects of AKBA on cell proliferation. Potential roles of AKBA in regulating the cell cycle, apoptosis, and autophagy in A549 were evaluated by flow cytometry, Western blotting, reverse transcription-polymerase chain reaction (PCR) and immunofluorescence (IF).
RESULTS: AKBA reduced cell viability in A549, H460, H1299, and BEAS-2B. In A549 cells, AKBA suppressed the clone formation, arrested the cell cycle at the G/G phase, induced cellular apoptosis. We found that AKBA suppressed the formation of autolysosome, and decreased the expression levels of Beclin-1, LC3A/B-I, and LC3A/B-II proteins. Furthermore, AKBA also inhibited the expression levels of PI3K/Akt signaling pathway proteins.
CONCLUSION: AKBA exerts the anti-cancer effects via cell cycle arrest, apoptosis induction, and autophagy suppression in NSCLC cells. This body of evidence supports the potential of AKBA as a promising drug in the treatment of NSCLC.
Onco Targets Ther. 2020;13():733-744.
PMID: 32158225 [PubMed - as supplied by publisher]
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| 54. |
β-Elemonic acid inhibits the growth of human Osteosarcoma through endoplasmic reticulum (ER) stress-mediated PERK/eIF2α/ATF4/CHOP activation and Wnt/β-catenin signal suppression.
Zhao A, Zhang Z, Zhou Y, Li X, Li X, Ma B, Zhang Q
BACKGROUND: Osteosarcoma (OS) is a significant threat to the lives of children and young adults. Although neoadjuvant chemotherapy is the first choice of treatment for OS, it is limited by serious side-effects and cancer metastasis. β-Elemonic acid (β-EA), an active component extracted from Boswellia carterii Birdw., has been reported to exhibit potential anti-inflammatory and anticancer activities. However, the anti-tumor effects and underlying mechanisms on OS as well as pharmacokinetic characteristics of β-EA remain unknown.
PURPOSE: This study was aimed to investigating the anti-tumor effects of β-EA on human OS, the underlying mechanisms, and the pharmacokinetic and tissue distribution characteristics.
STUDY DESIGN AND METHODS: Cell viability and colony formation assays were performed to determine the effect of β-EA cell on cell proliferation. Apoptosis rates, mitochondrial membrane potential and cell cycle features were analyzed by flow cytometry. qRT-PCR, Western blot, immunofluorescence and immunohistochemical assays were conducted to evaluate the expression levels of genes or proteins related to the pathways affected by β-EA in vitro and in vivo. Cell migration and invasion were evaluated in wound healing and Transwell chamber assays. The effects and pharmacokinetic characteristics of β-EA in vivo were evaluated by analyzing tumor suppression, pharmacokinetics and tissue distribution.
RESULTS: Explorations indicated that endoplasmic reticulum (ER) stress conditions provoked by β-EA activated the PERK/eIF2α/ATF4 branch of the unfolded protein reaction (UPR), stimulating C/EBP homologous protein (CHOP)-regulated apoptosis and inducing Ca leakage leading to caspase-dependent apoptosis. Furthermore, β-EA induced G0/G1 cell cycle arrest and inhibited metastasis of HOS and 143B cells by attenuating Wnt/β-catenin signaling effects, which included decreased levels of p-Akt(Ser473), p-Gsk3β (Ser9), Wnt/β-catenin target genes (c-Myc and CyclinD1) along with a decline in nuclear β-catenin accumulation. The fast absorption, short elimination half-life, and linear pharmacokinetic characteristics of β-EA were also revealed. The distribution of β-EA was detected in the tumor and bone tissues.
CONCLUSIONS: Overall, both in vitro and in vivo investigations showed the potential of β-EA for the treatment of human OS. The pharmacokinetic profile and considerable distribution in the tumor and bone tissues warrant further preclinical or even clinical studies.
Phytomedicine. 2020 Apr;69():153183.
PMID: 32113150 [PubMed - indexed for MEDLINE]
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| 55. |
3--Acetyl-11-keto- -boswellic acid ameliorated aberrant metabolic landscape and inhibited autophagy in glioblastoma.
Li W, Ren L, Zheng X, Liu J, Wang J, Ji T, Du G
Glioblastoma is the most common and aggressive primary tumor in the central nervous system, accounting for 12%-15% of all brain tumors. 3--Acetyl-11-keto--boswellic acid (AKBA), one of the most active ingredients of gum resin from Birdw., was reported to inhibit the growth of glioblastoma cells and subcutaneous glioblastoma. However, whether AKBA has antitumor effects on orthotopic glioblastoma and the underlying mechanisms are still unclear. An orthotopic mouse model was used to evaluate the anti-glioblastoma effects of AKBA. The effects of AKBA on tumor growth were evaluated using MRI. The effects on the alteration of metabolic landscape were detected by MALDI-MSI. The underlying mechanisms of autophagy reducing by AKBA treatment were determined by immunoblotting and immunofluorescence, respectively. Transmission electron microscope was used to check morphology of cells treated by AKBA. Our results showed that AKBA (100 mg/kg) significantly inhibited the growth of orthotopic U87-MG gliomas. Results from MALDI-MSI showed that AKBA improved the metabolic profile of mice with glioblastoma, while immunoblot assays revealed that AKBA suppressed the expression of ATG5, p62, LC3B, p-ERK/ERK, and P53, and increased the ratio of p-mTOR/mTOR. Taken together, these results suggested that the antitumor effects of AKBA were related to the normalization of aberrant metabolism in the glioblastoma and the inhibition of autophagy. AKBA could be a promising chemotherapy drug for glioblastoma.
Acta Pharm Sin B. 2020 Feb;10(2):301-312.
PMID: 32082975 [PubMed - as supplied by publisher]
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| 56. |
Anti-inflammatory and anti-cancer activities of frankincense: Targets, treatments and toxicities.
Efferth T, Oesch F
The oleogum resins of Boswellia species known as frankincense have been used for ages in traditional medicine in India, China and the Arabian world independent of its use for cultural and religious rituals in Europe. During the past two decades, scientific investigations provided mounting evidence for the therapeutic potential of frankincense. We conducted a systematic review on the anti-inflammatory and anti-cancer activities of Boswellia species and their chemical ingredients (e.g. 3-O-acetyl-11-keto-β boswellic acid, α- and β-boswellic acids, 11-keto-β-boswellic acid and other boswellic acids, lupeolic acids, incensole, cembrenes, triterpenediol, tirucallic acids, and olibanumols). Frankincense acts by multiple mechanisms, e.g. by the inhibition of leukotriene synthesis, of cyclooxygenase 1/2 and 5-lipoxygenase, of oxidative stress, and by regulation of immune cells from the innate and acquired immune systems. Furthermore, frankincense modulates signaling transduction responsible for cell cycle arrest and inhibition of proliferation, angiogenesis, invasion and metastasis. Clinical trials showed the efficacy of frankincense and its phytochemicals against osteoarthritis, multiple sclerosis, asthma, psoriasis and erythematous eczema, plaque-induced gingivitis and pain. Frankincense revealed beneficial effects towards brain tumor-related edema, but did not reduce glioma size. Even if there is no treatment effect on brain tumors itself, the management of glioma-associated edema may represent a desirable improvement. The therapeutic potential against other tumor types is still speculative. Experimental toxicology and clinical trials revealed only mild adverse side effects. More randomized clinical trials are required to estimate the full clinical potential of frankincense for cancer therapy.
Semin Cancer Biol. 2022 May;80():39-57.
PMID: 32027979 [PubMed - indexed for MEDLINE]
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| 57. |
Fractions of Suppress LTA, LTC, Cyclooxygenase-2 Activities and mRNA in HL-60 Cells and Reduce Lung Inflammation in BALB/c Mice.
Soni KK, Meshram D, Lawal TO, Patel U, Mahady GB
BACKGROUND: Purified fractions from a Boswellia serrata Roxb. Ex. Colebr. (Burseraceae) extract (ETOH and DCM) contain biologically active compounds that are well known for having inflammation inhibitory properties. In this work, the purified fractions were tested in-vitro for LTC, LTA and COX-2 activities using ELISA and qPCR was performed to determine gene regulation in human leukemia (HL-60) Cells. Two D-imaging tomography was performed to determine the anti-inflammatory activities of the fractions in BALB/c mouse model of lung inflammation.
OBJECTIVE: To evaluate anti-inflammatory activities of bioactive compounds of Boswellia serrata purified fractions.
METHODS: In-vitro MTT assay was performed in HL-60 cell lines for measuring the toxicity/ viability of the cells. ELISA tests were performed for evaluating LTA, LTC and COX-2 activities. qPCR was performed to evaluate the expression of mRNA in HL-60 cells. In-vivo experiments were performed in OVA sensitized and challenged BALB/c mice at two doses of Boswellia serrata purified fraction containing 6% Boswellic acid of 50 and 100mg/kg body weight were given orally and the standard drug dexamethasone (DXA, 4 mg/kg body weight) and reduction in lung inflammation was assessed by using an IVIS Xenogen in-vivo fluorescence imaging system.
RESULTS: A purified fraction of Boswellia serrata ETOH extracts reduced leukotriene-C-synthase activity by 52%, leuktotriene-A-hydrolase activity by 22% and COX-2 activity by 99% with an IC50 of 12.5μg/ml. Intragastric administration of the purified fraction of Boswellia serrata at two doses of 50mg/kg b.w. and 100mg/kg b.w., respectively along with 2-3% HPMC resulted in a ~51% (P value <0.01) reduction in OVA induced lung inflammation in BALB/c mice as observed by imaging tomography. Treatment of the OVA challenged mice with standard drug dexamethasone (DXA) reduced inflammation by ~66% with significant value (P<0.0001).
CONCLUSION: The present study describes that Boswellia serrata ethanolic extracts purified fraction (ETOH-BS) possess significant anti-inflammatory activities in HL-60 and in BALB/c and further supports for its use as Ayurvedic medicines traditionally in the treatment of lung disorders including allergy and asthma.
Curr Drug Discov Technol. 2021;18(1):95-104.
PMID: 31985381 [PubMed - indexed for MEDLINE]
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| 58. |
Cembrane-type diterpenoids from the gum resin of and their biological activities.
Sun X, Geng Y, Wang X, Qin D, Yu J
Eight new cembrane-type diterpenoids, boscartins AH-AK (1-8), along with two known ones (9-10), were isolated from the gum resin of . Compounds 1-3 were characteristic of high oxidation assignable to three epoxy groups, while compounds 4-8 were characteristic of two epoxy groups. Spectroscopic examination was used to elucidate their structures. All isolates were evaluated for antiproliferative activity against HCT-116 human colon cancer cells, anti-inflammatory activity against nitric oxide (NO) production, and hepatoprotective activity . All of them showed weak antiproliferative activity (IC > 100 μM), 8 exhibited potent inhibitory effects on NO production (IC of 14.8 μM), with the others showing weak anti-inflammatory activity (IC > 30 μM), and 1 exhibited more potent hepatoprotective activity than the positive control, bicyclol, at 10 μM against the damage induced by paracetamol in HepG2 cells.
RSC Adv. 2020 Jan;10(2):746-755.
PMID: 35494443 [PubMed - as supplied by publisher]
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| 59. |
Chemical Composition and in Vitro Cytotoxic Screening of Sixteen Commercial Essential Oils on Five Cancer Cell Lines.
Najar B, Shortrede JE, Pistelli L, Buhagiar J
The in vitro cytotoxic activity on human cancer cell lines of sixteen commercial EOs such as Aloysia citriodora, Boswellia sacra, Boswellia serrata, Cinnamomum zeylanicum, Cistus ladanifer, Citrus × aurantium, Citrus limon, Citrus sinensis, Cymbopogon citratus, Foeniculum vulgare, Illicium verum, Litsea cubeba, Satureja montana, Syzygium aromaticum, Thymus capitatus and Thymus vulgaris was performed using the MTT reduction assay. The screening was carried out on human cancer cells of breast adenocarcinoma (MCF7, T47D and MDA-MB-231), chronic myelogenous erythroleukemia (K562) and neuroblastoma cell lines (SH-SY5Y). C. zeylanicum and L. cubeba EOs were the most active on almost all the cell lines studied and thus could be promising as an anticancer agent. These two species showed a difference in their composition even though they belong to the Lauraceae family. Almost 57 % of the true cinnamon composition was made of (E)-cinnamaldehyde, while L. cubeba showed citral as the major compound (68.9 %). The K562 cells were the most sensitive to these oils with an IC ranging from 5.2 parts-per million (ppm) (C. zeylanicum) to 11.1 ppm (L. cubeba). The latter oil also showed an important cytotoxicity on MDA-MB-231 (13.4 ppm).
Chem Biodivers. 2020 Jan;17(1):e1900478.
PMID: 31713998 [PubMed - indexed for MEDLINE]
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| 60. |
Targeting Peptidyl-prolyl Cis-trans Isomerase NIMA-interacting 1: A Structure-based Virtual Screening Approach to Find Novel Inhibitors.
da Costa KS, Galúcio JM, de Jesus DA, Gomes GC, Lima E Lima AH, Taube PS, Dos Santos AM, Lameira J
BACKGROUND: Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1) is an enzyme that isomerizes phosphorylated serine or threonine motifs adjacent to proline residues. Pin1 has important roles in several cellular signaling pathways, consequently impacting the development of multiple types of cancers.
METHODS: Based on the previously reported inhibitory activity of pentacyclic triterpenoids isolated from the gum resin of Boswellia genus against Pin1, we designed a computational experiment using molecular docking, pharmacophore filtering, and structural clustering allied to molecular dynamics (MD) simulations and binding free energy calculations to explore the inhibitory activity of new triterpenoids against Pin1 structure.
RESULTS: Here, we report different computational evidence that triterpenoids from neem (Azadirachta indica A. Juss), such as 6-deacetylnimbinene, 6-Oacetylnimbandiol, and nimbolide, replicate the binding mode of the Pin1 substrate peptide, interacting with high affinity with the binding site and thus destabilizing the Pin1 structure.
CONCLUSIONS: Our results are supported by experimental data, and provide interesting structural insights into their molecular mechanism of action, indicating that their structural scaffolds could be used as a start point to develop new inhibitors against Pin1.
Curr Comput Aided Drug Des. 2020;16(5):605-617.
PMID: 31654518 [PubMed - indexed for MEDLINE]
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| 61. |
Comparative Investigation of Frankincense Nutraceuticals: Correlation of Boswellic and Lupeolic Acid Contents with Cytokine Release Inhibition and Toxicity against Triple-Negative Breast Cancer Cells.
Schmiech M, Lang SJ, Ulrich J, Werner K, Rashan LJ, Syrovets T, Simmet T
For centuries, frankincense extracts have been commonly used in traditional medicine, and more recently, in complementary medicine. Therefore, frankincense constituents such as boswellic and lupeolic acids are of considerable therapeutic interest. Sixteen frankincense nutraceuticals were characterized by high-performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS), revealing major differences in boswellic and lupeolic acid compositions and total contents, which varied from 0.4% to 35.7%. Frankincense nutraceuticals significantly inhibited the release of proinflammatory cytokines, such as TNF-α, IL-6, and IL-8, by LPS-stimulated peripheral blood mononuclear cells (PBMC) and whole blood. Moreover, boswellic and lupeolic acid contents correlated with TNF-α, IL-1β, IL-6, IL-8, and IL-10 inhibition. The nutraceuticals also exhibited toxicity against the human triple-negative breast cancer cell lines MDA-MB-231, MDA-MB-453, and CAL-51 in vitro. Nutraceuticals with total contents of boswellic and lupeolic acids >30% were the most active ones against MDA-MB-231 with a half maximal inhibitory concentration (IC) ≤ 7.0 µg/mL. Moreover, a frankincense nutraceutical inhibited tumor growth and induced apoptosis in vivo in breast cancer xenografts grown on the chick chorioallantoic membrane (CAM). Among eight different boswellic and lupeolic acids tested, β-ABA exhibited the highest cytotoxicity against MDA-MB-231 with an IC = 5.9 µM, inhibited growth of cancer xenografts in vivo, and released proinflammatory cytokines Its content in nutraceuticals correlated strongly with TNF-, IL-6, and IL-8 release inhibition.
Nutrients. 2019 Oct;11(10):.
PMID: 31581678 [PubMed - indexed for MEDLINE]
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| 62. |
Practical Application of "About Herbs" Website: Herbs and Dietary Supplement Use in Oncology Settings.
Hou YN, Deng G, Mao JJ
The Integrative Medicine Service at Memorial Sloan Kettering Cancer Center developed and maintains About Herbs (www.aboutherbs.com), which provides summaries of research data including purported uses, adverse effects, and herb-drug interactions for about 284 dietary supplements. Using Google Analytics, we found the website registered more than 26,317,000 hits since November 2002. The 10 most searched-for herbs/supplements of 2018 are chaga mushroom, turmeric, ashwagandha, reishi mushroom, graviola, Active Hexose-Correlated Compound, boswellia, dandelion, green tea, and Coriolus versicolor. Here we discuss their safety, herb-drug interactions, and appropriate uses in the oncology setting, based on literature searches in PubMed. Over the past 16 years, the evidence for use of these supplements is based mostly on preclinical findings, with few well-designed studies and limited trials conducted in cancer patients. It is important to familiarize health care professionals about popular supplements, so patients can be informed to make decisions that maximize benefits and minimize risks.
Cancer J. 2019;25(5):357-366.
PMID: 31567464 [PubMed - indexed for MEDLINE]
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| 63. |
α-Pinene Induces Apoptotic Cell Death via Caspase Activation in Human Ovarian Cancer Cells.
Hou J, Zhang Y, Zhu Y, Zhou B, Ren C, Liang S, Guo Y
BACKGROUND The plant-derived terpenoid, alpha-pinene is a bicyclic monoterpene potentially useful for the treatment of various diseases which also includes cancer and its types. The present investigation is about finding the anticancer activity of the alpha-pinene extracted from the leaves of Boswellia dalzielii over the PA-1 cancer cells of the human ovary. MATERIAL AND METHODS The cytotoxic activity of the alpha-pinene was evaluated using MTT and LDH assays which indicated that alpha-pinene could induce cytotoxicity in cancer-causing cells in the ovary. The consequences of alpha-pinene on the cell sequence regulation were determined by the staining technique using propidium iodide (PI) followed with flow cytometry. RESULTS The cell cycle distribution analysis showed that alpha-pinene inhibit the cycle progression from G₂ to M phase. In addition, apoptosis analysis is done through the double staining investigation using Annexin V-FITC/PI to analyze the controlled growth of alpha-pinene which is associated with the apoptosis. Caspase-3 a crucial enzyme involved in apoptosis was markedly increased in the a-pinene treated PA-1 cells. The apoptosis results reveal, that the cancer cells at the human ovary with alpha-pinene induces the significant populations of apoptotic cells. CONCLUSIONS Overall, alpha-pinene may exert anticancer effects in PA-1 cells by promoting cytotoxicity, suppression of cell sequence progression along with the programmed cell death.
Med Sci Monit. 2019 Sep;25():6631-6638.
PMID: 31482864 [PubMed - indexed for MEDLINE]
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| 64. |
In evaluation of apoptogenic potential and toxicological profile of triterpenoids.
Desai TH, Joshi SV
AIM: Caspases-3 and 8 are key mediators of intrinsic and extrinsic pathway of apoptosis, respectively. Triterpenoids of natural and synthetic origin reported as anticancer agents with apoptotic potential and hence may prove to be good candidates for testing against caspases-3 and 8.
MATERIALS AND METHODS: Various naturally-occurring and synthetic triterpenoids were subjected to activity prediction using PASS Online software, and among them, 67 compounds were selected for further processing. Protein structure of caspase-3 (3DEI) and caspase-8 (3KJQ) was obtained from the protein data bank and docked with selected triterpenoids using AutoDock Tools and AutoDock Vina. Toxicological profile was predicted based on clinical manifestations using PASS online software.
RESULTS: The high docking score of -10.0, -9.9, -9.8, and -9.5 were shown by friedelin, tingenone, albiziasaponin A, and albiziasaponin C, respectively, for caspase-3, and -11.0, -9.6, -9.6, and -9.4 by β-boswellic acid, bryonolic acid, canophyllic acid, and CDDO, respectively, for caspase-8. Possible adverse events were predicted with varying degree of probability and major relevant effects were reported. Hydrostatic interactions along with formation of hydrogen bonds with specific amino acids in the binding pocket were identified with each triterpenoid.
CONCLUSION: Lead molecules identified through this study such as friedelin, tingenone, albiziasaponin, bryonolic acid, and canophyllic acid may be utilized for further studies as apoptotic agents targeting caspases-3 and 8.
Indian J Pharmacol. 2019;51(3):181-207.
PMID: 31391686 [PubMed - indexed for MEDLINE]
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| 65. |
Bioactive cembrane-type diterpenoids from the gum-resin of Boswellia carterii.
Wang YG, Ren J, Ma J, Yang JB, Ji T, Wang AG
Chemical examination of the gum-resin of Boswellia carterii resulted in the isolation and characterization of eighteen new cembrane-type diterpenoids, named as Boscartins P-AG (1-18) and eight known ones. Their structures were established on the basis of extensive spectroscopic (2D NMR, IR, CD, MS and X-ray) analysis in combination with modified Mosher's method. All compounds featured unusual 1,12-oxygenated tetrahydrofuran functionalities, and were evaluated for hepatoprotective activity against D-galactosamine-induced HL-7702 cell damage and cytotoxic activity against MCF-7 human breast cancer cell in vitro. Compounds 1, 6-10, 12-13, 16-17 and 21-25 (10 μM) showed some hepatoprotective activity against D-galactosamine-induced HL-7702 cell damage.
Fitoterapia. 2019 Sep;137():104263.
PMID: 31295512 [PubMed - indexed for MEDLINE]
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| 66. |
Comparative Analysis of Pentacyclic Triterpenic Acid Compositions in Oleogum Resins of Different Species and Their In Vitro Cytotoxicity against Treatment-Resistant Human Breast Cancer Cells.
Schmiech M, Lang SJ, Werner K, Rashan LJ, Syrovets T, Simmet T
Pentacyclic triterpenic acids from oleogum resins of species are of considerable therapeutic interest. Yet, their pharmaceutical development is hampered by uncertainties regarding botanical identification and the complexity of triterpenic acid mixtures. Here, a highly sensitive, selective, and accurate method for the simultaneous quantification of eight boswellic and lupeolic acids by high-performance liquid chromatography with tandem mass spectrometry detection (HPLC-MS/MS) was developed. The method was applied to the comparative analysis of 41 oleogum resins of the species , , , , , , , , and . Multivariate statistical analysis of the data revealed differences in the triterpenic acid composition that could be assigned to distinct species and to their geographic growth location. Extracts of the oleogum resins exhibited cytotoxicity against the human, treatment-resistant, metastatic breast cancer cell line MDA-MB-231. Extracts from were the most potent ones with an average IC of 8.3 ± 0.6 µg/mL. The oleogum resin of the was further fractionated to enrich different groups of substances. The cytotoxic efficacy against the cancer cells correlates positively with the contents of pentacyclic triterpenic acids in extracts.
Molecules. 2019 Jun;24(11):.
PMID: 31181656 [PubMed - indexed for MEDLINE]
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| 67. |
Acetyl-11-keto-β-boswellic acid modulates membrane dynamics in benzo(a)pyrene-induced lung carcinogenesis.
Bhardwaj P, Kumar M, Dhatwalia SK, Garg ML, Dhawan DK
Membrane fluidity is the most important physiochemical property of cell membranes and governs its functional attributes. The current investigations were undertaken to understand the potential role of acetyl-11-keto-β-boswellic acid (AKBA), if any, on regulation of membrane dynamics under conditions of benzo(a)pyrene (BaP)-induced lung carcinogenesis in female rats. The animals were divided into five groups which included (I) Normal control, (II) Vehicle treated (olive oil), (III) BaP treated, (IV) AKBA treated and (V) BaP + AKBA treated. BaP was administered at a dose level of 50 mg/kg b.wt. in olive oil orally twice a week for 4 weeks. AKBA was given at a dose level of 50 mg/kg b.wt. in olive oil orally thrice a week for 24 weeks. In addition, AKBA was also administered at a similar dose to BaP-treated animals 4 weeks prior to BaP administration and continued for another 20 weeks. The lipid profile and membrane dynamics were analysed in lung tissue. Total lipids, phospholipids content, membrane fluidity, polarization and order of membrane were significantly (p ≤ 0.001) increased in BaP-exposed animals. However, significant decrease was observed in glycolipids, cholesterol, microviscosity and anisotropy levels compared with normal control animals. Appreciable improvements in above indices were recorded when AKBA was administered to BaP-treated animals. Moreover, the structural variations observed in Fourier-transform infrared spectroscopy spectrum were also normalized in BaP-treated rats with AKBA supplementation. This suggests that the AKBA has a potential role in improving membrane fluidity and associated lipid content in BaP-induced lung carcinogenesis.
Mol Cell Biochem. 2019 Oct;460(1-2):17-27.
PMID: 31165316 [PubMed - indexed for MEDLINE]
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| 68. |
Acetyl-11-keto-β-boswellic acid triggers premature senescence via induction of DNA damage accompanied by impairment of DNA repair genes in hepatocellular carcinoma cells in vitro and in vivo.
Wang S, Wang H, Sun B, Li D, Wu J, Li J, Tian X, Qin C, Chang H, Liu Y
Cellular senescence, a state of irreversible growth arrest, occurs in all somatic cells and causes the cells to exhaust replicative capacity. Recently, cellular senescence has been emerging as one of the principal mechanisms of tumor suppression, which can be induced by low doses of therapeutic drugs in cancer cells. Acetyl-11-keto-β-boswellic acid (AKBA), an active ingredient isolated from the plant Boswellia serrata, has been identified to induce apoptosis in hepatocellular carcinoma (HCC) cells. In this study, we found that low concentrations of AKBA treatment triggered cell growth arrest at G0/G1 phase with features of premature cellular senescence phenotype in both HCC cell lines HepG2 and SMMC7721, as observed by enlarged and flattened morphology, significant increase in cells with senescence-associated β-galactosidase staining, and decrease in cell proliferation and DNA synthesis. Furthermore, cellular senescence induced by AKBA occurred via activation of DNA damage response and impairment of DNA repair, as evidenced by strong induction of γH2AX and p53, and downregulated expressions of multiple DNA repair associated genes. Induction of p53 by AKBA caused a significant increase in p21 , which had a critical involvement in the induction of cellular senescence. Additionally, in vivo study demonstrated that induction of senescence contributed to the anticancer efficacy of AKBA. Therefore, our findings suggested that induction of premature senescence by AKBA through DNA damage response accompanied by impairment of DNA repair genes defines a novel mechanism contributing to its growth suppression in HCC cells.
Fundam Clin Pharmacol. 2020 Feb;34(1):65-76.
PMID: 31141202 [PubMed - indexed for MEDLINE]
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| 69. |
3-acetyl-11-keto-beta-boswellic acid decreases the malignancy of taxol resistant human ovarian cancer by inhibiting multidrug resistance (MDR) proteins function.
Jin L, Yingchun W, Zhujun S, Yinan W, Dongchen W, Hui Y, Xi Y, Wanzhou Z, Buluan Z, Jinhua W
OBJECTIVE: Recurrence of ovarian cancer is mainly due to multidrug resistance (MDR). 3-acetyl-11-keto-beta-boswellic acid (AKBA) could reverse the multidrug resistance in human ileocecal adenocarcinoma cells, but whether AKBA could modulate acquired MDR in ovarian cancer needs to be elucidated.
METHODS: The current study examined the effect of AKBA on ovarian cancer MDR using a Taxol resistant human ovarian cancer cell line A2780/Taxol. Cell proliferation, migration and invasion, the intracellular accumulation of Rhodamine 123 and expression of MDR proteins were studiedin vitro. Furthermore, the effect of AKBA on oncogenicity of A2780/Taxol cells in nude mice xenograft model was studied.
RESULTS: The results showed that apart from its cytostatic and apoptosis-induction effect, AKBA could restrain A2780/Taxol cell migration and invasion. In addition, AKBA improved the sensitivity of A2780/Taxol cells to Taxol apparently, and the reversal of MDR by AKBA was evident by increasing intracellular Rhodamine 123 in cells. Furthermore, the anti-cancer potential of AKBA was evidenced as that AKBA treatment significantly slowed tumor growth and decreased the expression of P-gp, LRP, BCRP and MRP.
CONCLUSION: Above results indicated that AKBA might be a potential compound to reverse MDR in human ovarian cancer.
Biomed Pharmacother. 2019 Aug;116():108992.
PMID: 31129513 [PubMed - indexed for MEDLINE]
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| 70. |
An Approach to Treatment of Liver Cancer by Novel Glycyrrhizin Derivative.
El-Senduny FF, Zidane MM, Youssef MM, Badria FA
BACKGROUND: Liver cancer is a life threating disease as it is the fifth most common cancer and the third most common cause of death worldwide with no safe, efficient, and economic drug available for treatment.
METHODS: This study intended to investigate glycyrrhizin and its derivatives for possible use as a cytotoxic agent and as a drug for liver cancer treatment. Thus, after treatment of liver cancer cell line HepG-2 with 50 μM of each compound, cell viability was determined.
RESULTS: The cytotoxicity assay showed glycyrrhizin derivatives ME-GA (18β-Glycyrrhetinic-30-methyl ester) and AKBA (3-acetyl-11- keto-β-Boswellic acid) to be the most potent drug against liver cancer cell line HepG-2 with IC50 values 25.50 ± 1.06 and 19.73 ± 0.89 μM, respectively. Both the compounds showed higher selectivity towards hepatocellular carcinoma rather than the normal lung fibroblast cell line WI-38. The presence of methyl ester at C-30 greatly increased the cytotoxicity of ME-GA which might be attributed to its higher activity and selectivity. Both ME-GA and AKBA contributed to inhibit cancer cell migration in the wound healing assay and impeded colony formation. The use of flow cytometry to carry out cell cycle analysis and the determination of possible mechanisms of action for apoptosis revealed that ME-GA arrested the cell cycle at G2/M that led to the inhibition of hepatocellular carcinoma and induced apoptosis via the extrinsic pathway and its ability to increase p53 transactivation.
CONCLUSION: This work highlights the cytotoxicity of glycyrrhizin and its derivatives for possible use as a chemotherapeutic agent against hepatocellular carcinoma cells HepG-2. The most cytotoxic compound was ME-GA (18β-Glycyrrhetinic-30-methyl ester) with no cytotoxic effect on the normal cell line. In summary, this new derivative may be used as an alternative or complementary medicine for liver cancer.
Anticancer Agents Med Chem. 2019;19(15):1863-1873.
PMID: 30973113 [PubMed - indexed for MEDLINE]
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| 71. |
New derivatives of 11-keto-β-boswellic acid (KBA) induce apoptosis in breast and prostate cancers cells.
Bini Araba A, Ur Rehman N, Al-Araimi A, Al-Hashmi S, Al-Shidhani S, Csuk R, Hussain H, Al-Harrasi A, Zadjali F
A series of new 11-keto-β-boswellic acid were partially-synthesized by modifying the hydroxyl and carboxylic acid functional groups of ring A. The structures of the new analogs were confirmed by detailed spectral data analysis. Compounds , and exhibited potent anti-cancer results against two human tumor cancer cell lines having IC value of MCF-7 (breast) and LNCaP (prostate): 123.6, 9.6 and 88.94 μM and 9.6, 44.12 and 12.03 μM, respectively. Additionally, a maximum nuclear fragmentation was observed for (78.44%) in AKBA treated cells after 24 hr followed by and with (74.25 and 66.9% respectively). This study suggests that the presence of hydrazone functionality ( and ) has effectively improved the potency of AKBA. Interestingly, compound with a lost carboxylic acid group of ring A showed comparable potent activity. Highly selective AKBA requires further modification to improve its bioavailability and solubility inside the cancer cells.
Nat Prod Res. 2021 Mar;35(5):707-716.
PMID: 30931626 [PubMed - indexed for MEDLINE]
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| 72. |
Boswellic acid has anti-inflammatory effects and enhances the anticancer activities of Temozolomide and Afatinib, an irreversible ErbB family blocker, in human glioblastoma cells.
Barbarisi M, Barbarisi A, De Sena G, Armenia E, Aurilio C, Libutti M, Iaffaioli RV, Botti G, Maurea N, Quagliariello V
Phytother Res. 2019 Jun;33(6):1670-1682.
PMID: 30924205 [PubMed - indexed for MEDLINE]
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| 73. |
Interplay of non-coding RNAs and approved antimetabolites such as gemcitabine and pemetrexed in mesothelioma.
Biersack B
Gemcitabine and pemetrexed are clinically approved antimetabolites for the therapy of mesothelioma diseases. These drugs are often applied in combination with platinum complexes and other drugs. The activity of antimetabolites depended on the expression levels of certain non-coding RNAs, in particular, of small microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). The development of tumor resistance towards antimetabolites was regulated by non-coding RNAs. An overview of the interplay between gemcitabine/pemetrexed antimetabolites and non-coding RNAs in mesothelioma is provided. Further to this, various non-coding RNA-modulating agents are discussed which displayed positive effects on gemcitabine or pemetrexed treatment of mesothelioma diseases. A detailed knowledge of the connections of non-coding RNAs with antimetabolites will be constructive for the design of improved therapies in future.
Noncoding RNA Res. 2018 Dec;3(4):213-225.
PMID: 30809600 [PubMed - as supplied by publisher]
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| 74. |
Relations between approved platinum drugs and non-coding RNAs in mesothelioma.
Biersack B
Malignant mesothelioma diseases feature an increasing risk due to their severe forms and their association with asbestos exposure. Platinum(II) complexes such as cisplatin and carboplatin are clinically approved for the therapy of mesothelioma often in combination with antimetabolites such as pemetrexed or gemcitabine. It was observed that pathogenic properties of mesothelioma cells and the response of mesothelioma tumors towards platinum-based drugs are strongly influenced by non-coding RNAs, in particular, by small microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). These non-coding RNAs controlled drug sensitivity and the development of tumor resistance towards platinum drugs. An overview of the interactions between platinum drugs and non-coding RNAs is given and the influence of non-coding RNAs on platinum drug efficacy in mesothelioma is discussed. Suitable non-coding RNA-modulating agents with potentially beneficial effects on cisplatin treatment of mesothelioma diseases are mentioned. The understanding of mesothelioma diseases concerning the interactions of non-coding RNAs and platinum drugs will optimize existing therapy schemes and pave the way to new treatment options in future.
Noncoding RNA Res. 2018 Dec;3(4):161-173.
PMID: 30809599 [PubMed - as supplied by publisher]
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| 75. |
Synthesis of new boswellic acid derivatives as potential antiproliferative agents.
Shamraiz U, Hussain H, Ur Rehman N, Al-Shidhani S, Saeed A, Khan HY, Khan A, Fischer L, Csuk R, Badshah A, Al-Rawahi A, Hussain J, Al-Harrasi A
In the current investigation, a series of heterocyclic derivatives of boswellic acids were prepared along with new monomers of 3--acetyl-11-keto-β-boswellic acid (AKBA, ) 11-keto-β-boswellic acid (KBA, ) and several new bis-AKBA and KBA homodimers and AKBA-KBA heterodimers. The effects of these compounds on the proliferation of different human cancer cell lines, viz., FaDu (pharynx carcinoma), A2780 (ovarian carcinoma), HT29 (colon adenocarcinoma), and A375 (malignant melanoma), have been evaluated. Thus, KBA homodimer effectively inhibited the growth of FaDu, A2780, HT29, and A375 cells with EC values below 9 μM. In addition, compounds , , , , , and also exhibited cytotoxic effects for A2780, HT29, and A375 cancer cells. In particular, the pyrazine analog was highly cytotoxic for A375 cancer cells with an EC value of 2.1 μM.
Nat Prod Res. 2020 Jul;34(13):1845-1852.
PMID: 30691289 [PubMed - indexed for MEDLINE]
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| 76. |
Boswellia frereana suppresses HGF-mediated breast cancer cell invasion and migration through inhibition of c-Met signalling.
Parr C, Ali AY
BACKGROUND: Hepatocyte growth factor (HGF) plays a pivotal role in breast cancer cell motility, invasion and angiogenesis. These pro-metastatic events are triggered through HGF coupling and activation of the c-Met receptor. Reports have demonstrated that HGF/c-Met signalling plays an important part in breast cancer progression and that their expression is linked to poor patient outcome. In the present study, we investigated the anti-metastatic potential of an extract from traditional Somalian frankincense, Boswellia frereana, on human breast cancer cells. In addition, we also examined the effect of this Boswellia frereana extract (BFE) upon HGF-mediated stimulation of the c-Met receptor.
METHODS: Two triple negative human breast cancer cell lines, BT549 and MDA-MB-231, were utilised in the study to examine the effect of BFE on tumour cell proliferation, migration, matrix-adhesion, angiogenesis and invasion. Cell migration was investigated using a Cell IQ time-lapsed motion analysis system; while tumour cell-matrix adhesion, angiogenesis and invasion were assessed through Matrigel-based in vitro assays. Breast cancer cell growth and spheroid formation was examined through proliferation assay and 3D non-scaffold cell culture techniques. Western Blotting was employed to determine the phosphorylation status of the c-Met receptor tyrosine kinase following BFE treatment and subsequent HGF stimulation.
RESULTS: Following HGF treatment, the breast cancer cells displayed a significant increase in migration, matrix adhesion, vessel/tubule formation, invasion and c-Met activation. HGF did not appear to have any bearing on the proliferation rate or spheroid formation of these breast cancer cells. The addition of the BFE extract quenched the HGF-enhanced migratory, angiogenic and invasive potential of these cells. Further study revealed that BFE inhibited c-Met receptor tyrosine kinase phosphorylation within these breast cancer cells.
CONCLUSIONS: Our findings reveal that BFE was able to significantly suppress the influence of HGF in breast cancer cell motility and invasion in vitro, through the ability of BFE to reduce HGF/c-Met signalling events. Therefore, these results indicate that BFE could play a novel role in the treatment of breast cancer.
J Transl Med. 2018 Oct;16(1):281.
PMID: 30314527 [PubMed - indexed for MEDLINE]
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| 77. |
Retraction: Boswellic Acid Blocks Signal Transducers and Activators of Transcription 3 Signaling, Proliferation, and Survival of Multiple Myeloma via the Protein Tyrosine Phosphatase SHP-1.
Mol Cancer Res. 2018 Sep;16(9):1444.
PMID: 30181208 [PubMed - as supplied by publisher]
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| 78. |
Acetyl-11-keto-β-boswellic acid suppresses docetaxel-resistant prostate cancer cells in vitro and in vivo by blocking Akt and Stat3 signaling, thus suppressing chemoresistant stem cell-like properties.
Liu YQ, Wang SK, Xu QQ, Yuan HQ, Guo YX, Wang Q, Kong F, Lin ZM, Sun DQ, Wang RM, Lou HX
Acquired docetaxel-resistance of prostate cancer (PCa) remains a clinical obstacle due to the lack of effective therapies. Acetyl-11-keto-β-boswellic acid (AKBA) is a pentacyclic triterpenic acid isolated from the fragrant gum resin of the Boswellia serrata tree, which has shown intriguing antitumor activity against human cell lines established from PCa, colon cancer, malignant glioma, and leukemia. In this study, we examined the effects of AKBA against docetaxel-resistant PCa in vitro and in vivo as well as its anticancer mechanisms. We showed that AKBA dose-dependently inhibited cell proliferation and induced cell apoptosis in docetaxel-resistant PC3/Doc cells; its IC value in anti-proliferation was ∼17 μM. Furthermore, AKBA dose-dependently suppressed the chemoresistant stem cell-like properties of PC3/Doc cells, evidenced by significant decrease in the ability of mammosphere formation and down-regulated expression of a number of stemness-associated genes. The activation of Akt and Stat3 signaling pathways was remarkably enhanced in PC3/Doc cells, which contributed to their chemoresistant stem-like phenotype. AKBA (10-30 μM) dose-dependently suppressed the activation of Akt and Stat3 signaling pathways in PC3/Doc cells. In contrast, overexpression of Akt and Stat3 significantly attenuated the inhibition of AKBA on PC3/Doc cell proliferation. In docetaxel-resistant PCa homograft mice, treatment with AKBA significantly suppresses the growth of homograft RM-1/Doc, equivalent to its human PC3/Doc, but did not decrease their body weight. In summary, we demonstrate that AKBA inhibits the growth inhibition of docetaxel-resistant PCa cells in vitro and in vivo via blocking Akt and Stat3 signaling, thus suppressing their cancer stem cell-like properties.
Acta Pharmacol Sin. 2019 May;40(5):689-698.
PMID: 30171201 [PubMed - indexed for MEDLINE]
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| 79. |
Design, synthesis and biological evaluation of ring A modified 11-keto-boswellic acid derivatives as Pin1 inhibitors with remarkable anti-prostate cancer activity.
Huang M, Li A, Zhao F, Xie X, Li K, Jing Y, Liu D, Zhao L
Pin1 (Protein interaction with never in mitosis A1) is a validated molecular target for anticancer drug discovery. Herein, we reported the design, synthesis, and structure-activity relationship study of novel ring A modified AKBA (3-acetyl-11-keto-boswellic acid) derivatives as Pin1 inhibitors. Most compounds showed superior Pin1 inhibitory activities to AKBA. One of the most promising compounds, 10a, potently inhibited Pin1 with IC value of 0.46 μM, while it displayed excellent anti-proliferative effect against prostate cancer cells PC-3 with GI value of 1.82 μM. Structure-activity relationship indicated that reasonable structural modifications in ring A had significant impact on improving activity. Further mechanism research revealed that 10a decreased the level of Cyclin D1 and caused cell cycle arrest at G0/G1 phase in PC-3 cancer cells. Thus, compound 10a may serve as potential anti-prostate cancer agent for further investigation through Pin1 inhibition.
Bioorg Med Chem Lett. 2018 Oct;28(19):3187-3193.
PMID: 30153964 [PubMed - indexed for MEDLINE]
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| 80. |
Review of Common Alternative Herbal "Remedies" for Skin Cancer.
Li JY, Kampp JT
BACKGROUND: Alternative herbal remedies for skin cancer are commonly found on the Internet. Many websites contain inaccurate or false information regarding side effects and efficacy.
OBJECTIVE: To review the evidence behind several commonly advertised herbal remedies that claim to cure skin cancer: black salve, eggplant, frankincense, cannabis, black raspberry, milk thistle, St. John's wort, and turmeric.
METHODS: A PubMed search was performed using the common and scientific names of frequently advertised herbal remedies along with the terms "nonmelanoma skin cancer," or "basal cell carcinoma" or "squamous cell carcinoma," or "melanoma."
RESULTS: Some preclinical studies have shown positive evidence that these substances can induce apoptosis in skin cancer, but clinical studies proving efficacy are either insufficient, nonexistent, or show negative evidence. Botanicals that were excluded are those that do not have published studies of their efficacy as skin cancer treatments.
CONCLUSION: Online advertising may tempt patients to use botanical agents while citing efficacy found in preclinical studies. However, many agents lack strong clinical evidence of efficacy. Dermatologists must be aware of common herbal alternatives for skin cancer treatment to maintain effective patient communication and education.
Dermatol Surg. 2019 Jan;45(1):58-67.
PMID: 30096105 [PubMed - indexed for MEDLINE]
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| 81. |
Chemoprevention of inflammation-related colorectal cancer by silymarin-, acetyl-11-keto-beta-boswellic acid-, curcumin- and maltodextrin-enriched dietetic formulation in animal model.
Girardi B, Principi M, Pricci M, Giorgio F, Iannone A, Losurdo G, Ierardi E, Di Leo A, Barone M
On the basis of preliminary in vitro experience, we assessed whether an enriched nutritional formulation with estrogen receptor (ER)-beta agonist and anti-inflammatory properties may prevent inflammation-associated colorectal cancer (CRC) in an animal model. Study sample enclosed 110 C57BL/6J male mice. Forty underwent dietary supplement safety assessment (20 standard diet and 20 enriched formulation). Seventy were treated with azoxymethane (AOM)/dextran sulfate sodium and divided into two groups: 35 received standard diet and 35 enriched formulation (curcumin, boswellic acids, silymarin and maltodextrins). Miniature colonoscopy demonstrated colitis and solid lesion development in five mice/group 100 days after first AOM injection. Mice were killed after 10 days. In each group, four subgroups received intraperitoneal bromodeoxyuridine (BrdU) injection at 24th/48th/72nd/96th hour before killing. Anti-inflammatory effect and chemoprevention were evaluated by lesion number/size, histological inflammation/dysplasia/neoplasia assessment, pro-inflammatory cytokine messenger RNA (mRNA), ER-beta/ER-alpha/BrdU immunohistochemistry and TUNEL immunofluorescence. Standard formulation assumption was associated with colon shortening compared with enriched one (P = 0.04), which reduced solid lesion number and size (P < 0.001 for both), histological inflammation score (P = 0.04), pro-inflammatory cytokine mRNA expression (P < 0.001), number of low-grade dysplasia (LGD; P = 0.03) and high-grade dysplasia (P < 0.001) areas. CRC was observed in 69.6% in standard and 23.5% in enriched formulation assuming animals (P < 0.001). Enriched formulation induced lower ER-alpha expression in CRC (P < 0.001) and higher ER-beta expression in LGD (P < 0.001) being associated to higher epithelial turnover (BrdU; P<0.001) in normal mucosa and increased apoptosis in LGD and CRC (P < 0.001 for both). Our results are promising for a successful anti-inflammatory and chemopreventive effect of enriched formulation in CRC arising from inflamed tissue.
Carcinogenesis. 2018 Oct;39(10):1274-1282.
PMID: 30084990 [PubMed - indexed for MEDLINE]
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| 82. |
3-O-acetyl-11-keto-β-boswellic acid exerts anti-tumor effects in glioblastoma by arresting cell cycle at G2/M phase.
Li W, Liu J, Fu W, Zheng X, Ren L, Liu S, Wang J, Ji T, Du G
BACKGROUND: Glioblastoma (GBM) is the most common, malignant, and lethal primary brain tumor in adults accounting for about 50% of all gliomas. Up to now, the chemotherapy approaches for GBM were limited. 3-O-acetyl-11-keto-β-boswellic acid (AKBA), the major active ingredient of the gum resin from Boswellia serrata and Boswellia carteri Birdw., was reported to inhibit the growth of many types of cancer cells; however, the underlying mechanism of its anticancer effects are still unclear.
METHODS: The effects of AKBA on cell viability and its cytotoxicity were determined using CCK8 and LDH kits respectively. The EdU-DNA synthesis assay was used to evaluate inhibition of cell proliferation by AKBA. The role of AKBA in glioblastoma cell functions such as migration/invasion, and colony formation was evaluated using transwell chambers and soft agar, respectively. Flow cytometry and western blotting were used to detect AKBA-induced apoptosis. Potential mechanisms of AKBA action were explored by RNA sequencing and the identified hub genes were validated by real-time quantitative PCR and western blotting. Finally, the in vivo anti-tumor activity of AKBA was evaluated against a human glioblastoma cell line, U87-MG, in a xenograft mouse model.
RESULTS: AKBA inhibited cell proliferation, caused the release of LDH, decreased DNA synthesis, and inhibited the migration, invasion, and colony formation of U251 and U87-MG human glioblastoma cell lines. AKBA increased apoptosis as well as the activity of caspase 3/7 and the protein expression of cleaved-caspase 3 and cleaved PARP, while decreasing mitochondrial membrane potential. RNA-sequencing analyses showed that AKBA suppressed the expression of pRB, FOXM1, Aurora A, PLK1, CDC25C, p-CDK1, cyclinB1, Aurora B, and TOP2A while increasing the expression of p21 and GADD45A. These findings were validated by qRT-PCR and western blotting. The data are consistent with a mechanism in which AKBA arrested the cell cycle in glioblastoma cells at the G2/M phase by regulating the p21/FOXM1/cyclin B1 pathway, inhibited mitosis by downregulating the Aurora B/TOP2A pathway, and induced mitochondrial-dependent apoptosis. Oral administration of AKBA (100 mg/kg) significantly suppressed the tumorigenicity of U87-MG cells in a xenograft mouse model.
CONCLUSIONS: Taken together, these results suggest that AKBA (molecular weight, 512.7 Da) might be a promising chemotherapy drug in the treatment of GBM.
J Exp Clin Cancer Res. 2018 Jul;37(1):132.
PMID: 29970196 [PubMed - indexed for MEDLINE]
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| 83. |
Combined acetyl-11-keto-β-boswellic acid and radiation treatment inhibited glioblastoma tumor cells.
Conti S, Vexler A, Edry-Botzer L, Kalich-Philosoph L, Corn BW, Shtraus N, Meir Y, Hagoel L, Shtabsky A, Marmor S, Earon G, Lev-Ari S
Glioblastoma multiforme (GBM) is the most common and most aggressive subtype of malignant gliomas. The current standard of care for newly diagnosed GBM patients involves maximal surgical debulking, followed by radiation therapy and temozolomide chemotherapy. Despite the advances in GBM therapy, its outcome remains poor with a median survival of less than two years. This poor outcome is partly due to the ability of GBM tumors to acquire adaptive resistance to therapy and in particular to radiation. One of the mechanisms contributing to GBM tumor progression and resistance is an aberrant activation of NF-ĸB, a family of inducible transcription factors that play a pivotal role in regulation of many immune, inflammatory and carcinogenic responses. Acetyl-11-keto-β-boswellic acid (AKBA) is a pentacyclic terpenoid extracted from the gum Ayurvedic therapeutic plant Boswellia serrata. AKBA is anti-inflammatory agent that exhibits potent cytotoxic activities against various types of tumors including GBM. One of the mechanisms underlying AKBA anti-tumor activity is its ability to modulate the NF-ĸB signaling pathway. The present study investigated in vitro and in vivo the effect of combining AKBA with ionizing radiation in the treatment of GBM and assessed AKBA anti-tumor activity and radio-enhancing potential. The effect of AKBA and/or radiation on the survival of cultured glioblastoma cancer cells was evaluated by XTT assay. The mode of interaction of treatments tested was calculated using CalcuSyn software. Inducing of apoptosis following AKBA treatment was evaluated using flow cytometry. The effect of combined treatment on the expression of PARP protein was analysed by Western blot assay. Ectopic (subcutaneous) GBM model in nude mice was used for the evaluation of the effect of combined treatment on tumor growth. Immunohistochemical analysis of formalin-fixed paraffin-embedded tumor sections was used to assess treatment-related changes in Ki-67, CD31, p53, Bcl-2 and NF-ĸB-inhibitor IĸB-α. AKBA treatment was found to inhibit the survival of all four tested cell lines in a dose dependent manner. The combined treatment resulted in a more significant inhibitory effect compared to the effect of treatment with radiation alone. A synergistic effect was detected in some of the tested cell lines. Flow cytometric analysis with Annexin V-FITC/PI double staining of AKBA treated cells indicated induction of apoptosis. AKBA apoptotic activity was also confirmed by PARP cleavage detected by Western blot analysis. The combined treatment suppressed tumor growth in vivo compared to no treatment and each treatment alone. Immunohistochemical analysis showed anti-angiogenic and anti-proliferative activity of AKBA in vivo. It also demonstrated a decrease in p53 nuclear staining and in Bcl-2 staining and an increase in IĸB-α staining following AKBA treatment both alone and in combination with radiotherapy. In this study, we demonstrated that AKBA exerts potent anti-proliferative and apoptotic activity, and significantly inhibits both the survival of glioblastoma cells in vitro and the growth of tumors generated by these cells. Combination of AKBA with radiotherapy was found to inhibit factors which involved in cell death regulation, tumor progression and radioresistence, therefore it may serve as a novel approach for GBM patients.
PLoS One. 2018;13(7):e0198627.
PMID: 29969452 [PubMed - indexed for MEDLINE]
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| 84. |
Homopiperazine-rhodamine B adducts of triterpenoic acids are strong mitocans.
Wolfram RK, Fischer L, Kluge R, Ströhl D, Al-Harrasi A, Csuk R
Parent pentacyclic triterpenoic acids such as ursolic-, oleanolic, glycyrrhetinic, betulinic and boswellic acid were converted into their acetylated piperazinyl amides that were coupled with rhodamine B. SRB assays to evaluate their cytotoxicity showed all of these triterpene-homopiperazinyl-rhodamine adducts 16-20 being highly cytotoxic for a panel of human tumor cell lines even in nanomolar concentrations while being significantly less cytotoxic for non-malignant cells. Interestingly enough, these compounds were even more cytotoxic than previously prepared piperazinyl analogs, thus making the homopiperazinyl spacer a very interesting scaffold for the development of biologically active compounds. Extra staining experiments showed that the cytostatic effect of compounds 18 and 20 onto A2780 cancer cells is due to their ability to act as a mitocan.
Eur J Med Chem. 2018 Jul;155():869-879.
PMID: 29960206 [PubMed - indexed for MEDLINE]
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| 85. |
Inhibitory effect of 11-carbonyl-beta-boswellic acid on non-small cell lung cancer H446 cells.
Huang G, Yang J, Zhang L, Cao L, Zhang M, Niu X, Zhou Z, Zhang X, Li P, Liu JF
BACKGROUND: The anti-lung tumor potential of 11-carbonyl-β-boswellic acid was investigated.
MATERIALS & METHODS: The inhibitory effects of 11-carbonyl-β-boswellic acid on non-small cell lung cancer (NSCLC) was assessed by proliferation, apoptosis, cell cycle and molecular mechanisms in NSCLC H446 cells in vitro. The results showed that the growth of H446 cells was significantly inhibited by 11-carbonyl-β-boswellic acid in a dose- and time-dependent manner. Meanwhile, 11-carbonyl-β-boswellic acid induced cell apoptosis and cell cycle G2-M phase arrest in H446 cells.
RESULTS: Mechanistically, 11-carbonyl-β-boswellic acid could activate JNK signaling pathway, down-regulate the expression of surviving protein, and activate the cleavage of PARP, leading to marked inhibitory effect on H446 cells.
CONCLUSIONS: These findings suggest that 11-carbonyl-β-boswellic acid may be a potential usefulness for preventing and treatment of NSCLC.
Biochem Biophys Res Commun. 2018 Sep;503(4):2202-2205.
PMID: 29953860 [PubMed - indexed for MEDLINE]
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| 86. |
Boswellic acid exerts potent anticancer effects in HCT-116 human colon cancer cells mediated via induction of apoptosis, cell cycle arrest, cell migration inhibition and inhibition of PI3K/AKT signalling pathway.
Wang D, Ge S, Bai J, Song Y
PURPOSE: Boswellic acid is an important plant-derived natural product with tremendous pharmacological potential and has been reported to inhibit the growth of several types of cancer cells. In this study we report the anticancer activity of boswellic acid against human colon cancer cells via induction of apoptosis, cell cycle arrest and inhibition of cell migration and PI3K/AKT signalling pathway.
METHODS: The antiproliferative effects of boswellic acid were assessed by MTT assay using different doses of the drug. The apoptotic effects were studied by DAPI and annexin V/PI staining assays, and cell cycle distribution was studied by flow cytometry. The effects of the drug on PI3K/AKT protein expression were studied using western blot analysis.
RESULTS: The results of this study showed that boswellic acid suppresses the growth of HCT-116 colon cancer cells. The anticancer effects were found to be dose-dependent and the IC50 value was 15 μM against the HCT-116 colon cancer cells. The inhibition of growth of these cancer cells was mainly due to apoptosis and G2/M cell cycle arrest. Besides, boswellic acid altered the Bax/Bcl-2 ratio in the HCT-116 cancer cells and inhibited their migration as indicated by the cell migration assay. It was observed that boswellic acid decreased the expression of p-PI3K and p-AKT in a concentration- dependent manner. However, the expression of PI3K and AKT remained almost unaltered.
CONCLUSION: In conclusion, these results clearly suggest that boswellic acid could be employed in the treatment of colon cancer provided further in vivo and other in depth experiments are done.
J BUON. 2018;23(2):340-345.
PMID: 29745074 [PubMed - indexed for MEDLINE]
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| 87. |
Utilizing biomarkers in colorectal cancer: an interview with Ajay Goel.
Goel A
Ajay Goel speaks to Rachel Jenkins, Commissioning Editor. Ajay Goel, PhD, is a Professor and Director, Center for Gastrointestinal Research, and Director, Center for Translational Genomics and Oncology, at the Baylor Scott & White Research Institute, Baylor University Medical Center in Dallas, Texas. Dr Goel has spent more than 20 years researching cancer and has been the lead author or contributor to over 240 scientific articles published in peer-reviewed international journals and several book chapters. He is also a primary inventor on more than 15 international patents aimed at developing various biomarkers for the diagnosis, prognosis and prediction of gastrointestinal cancers. He is currently using advanced genomic and transcriptomic approaches to develop novel DNA- and miRNA-based biomarkers for the early detection of colorectal cancers. In addition, he is researching the prevention of gastrointestinal cancers using integrative and alternative approaches, including botanical products such as curcumin (from turmeric) and boswellia. Dr Goel is a member of the American Association for Cancer Research (AACR) and the American Gastroenterology Association (AGA) and is on the international editorial boards of several journals including Gastroenterology, Clinical Cancer Research, Carcinogenesis, PLoS ONE, Scientific Reports, Epigenomics, Future Medicine, Alternative Therapies in Heath and Medicine and World Journal of Gastroenterology. He is also actively involved in peer-reviewing activities for more than 100 international scientific journals and various grant review panels of various national and international funding organizations. His research has been actively funded by various private and federal organizations, including funding from the National Cancer Institute (NCI) at the NIH, American Cancer Society (ACS) and other state organizations. He has won more than dozen awards and honors, including the Union of European Gastroenterology Federation's Distinguished Researcher Award, multiple Poster of Distinction Awards from the AGA, and Visiting Professorships from various national and international academic institutions and academic bodies. Some of his key research interests include: Understanding the basic genetics and epigenetic basis of gastrointestinal cancers; Use of epigenetic markers, both DNA and RNA, for the early detection of colorectal, pancreatic and other gastrointestinal cancers; Personalized medicine and treatment of gastrointestinal cancers; Chemoprevention, using complementary and alternative approaches using nutraceuticals such as curcumin, green tea, resveratrol and other botanicals.
Future Oncol. 2017 Dec;13(28):2511-2514.
PMID: 29168653 [PubMed - indexed for MEDLINE]
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| 88. |
Transcriptomic Profiling of MDA-MB-231 Cells Exposed to and 3-O-Acetyl-B-Boswellic Acid; ER/UPR Mediated Programmed Cell Death.
Mazzio EA, Lewis CA, Soliman KFA
BACKGROUND/AIM: Triple-negative breast cancer (TNBC) is characterized by the absence of hormone receptors (estrogen, progesterone and human epidermal growth factor receptor-2) and a relatively poor prognosis due to inefficacy of hormone receptor-based chemotherapies. It is imperative that we continue to explore natural products with potential to impede growth and metastasis of TNBC. In this study, we screened over 1,000 natural products for capacity to induce cell death in TNBC (MDA-MB -231) cells.
MATERIALS AND METHODS: Frankincense (Boswellia serrata extract (BSE)) and 3-O-Acetyl-β-boswellic acid (3-OAβBA) were relatively potent, findings that corroborate the body of existing literature. The effects of BSE and 3-OAβBA on genetic parameters in MDA-MB-231 cells were evaluated by examining whole-transcriptomic influence on mRNAs, long intergenic non-coding RNA transcripts (lincRNA) and non-coding miRNAs.
RESULTS: Bio-statistical analysis demarcates the primary effect of both BSE/3-OAβBA on the up-regulation of PERK (protein kinase RNA-like endoplasmic reticulum kinase)- endoplasmic reticulum (ER)/unfolded protein response (UPR) pathways that are closely tied to activated programmed cell death (APCD). Global profiling confirms concomitant effects of BSE/3-OAβBA on upwardly expressed ER/URP APCD key components PERK (EIF2AK3), XBP1, C/EBP homologous protein transcription factor (CHOP), ATF3 and DDIT3,4/DNA-damage-inducible transcript 3,4 (GADD34). Further, BSE and/or 3-OAβBA significantly down-regulated oncogenes (OG) which, heretofore, lack functional pathway mapping, but are capable of driving epithelial-mesenchymal transition (EMT), cell survival, proliferation, metastasis and drug resistance. Among these are cell migration-inducing protein hyaluronan binding (CEMIP) [-7.22]; transglutaminase 2 [-4.96], SRY box 9 (SOX9) [-4.09], inhibitor of DNA binding 1, dominant negative helix-loop-helix protein (ID1) [-6.56]; and endothelin 1 (EDN1, [-5.06]). Likewise, in the opposite manner, BSE and/or 3-OAβBA induced the robust overexpression of tumor suppressor genes (TSGs), including: glutathione-depleting ChaC glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1) [+21.67]; the mTOR inhibitors - sestrin 2 (SESN2) [+16.4] Tribbles homolog 3 (TRIB3) [+6.2], homocysteine-inducible, endoplasmic reticulum stress-inducible, ubiquitin-like domain member 1 (HERPUD1) [+12.01]; and cystathionine gamma-lyase (CTH) [+11.12].
CONCLUSION: The anti-cancer effects of the historically used frankincense sap (BSE) appear to involve major impact on the ER/UPR response, concomitant to effecting multiple targets counter to the growth, proliferation and metastasis of TNBC cancer cells. The microarray data are available at Expression Omnibus GEO Series accession number GSE102891.
Cancer Genomics Proteomics. 2017;14(6):409-425.
PMID: 29109091 [PubMed - indexed for MEDLINE]
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| 89. |
Methanolic extract of Boswellia serrata exhibits anti-cancer activities by targeting microsomal prostaglandin E synthase-1 in human colon cancer cells.
Ranjbarnejad T, Saidijam M, Moradkhani S, Najafi R
BACKGROUND: Colorectal cancer (CRC) is the most common cancer. A proper method to reduce mortality of CRC is chemoprevention to prevent initiation and promotion of intestinal tumorgenesis. One of the promising and developing chemopreventive agents is natural compounds found in plants. Frankincense, the resin extract from the Boswellia specious, has been used in traditional and modern medicine for treating various diseases with very minimal side effects. In the current study, we investigated the anti-cancer activity of methanolic extract of Boswellia serrata (B. serrata) on HT-29 human colon cancer cells.
METHODS: HT-29 cells were treated with different concentrations of B. serrata and cell viability was assessed by MTT assay. mRNA expression of microsomal prostaglandin E synthase-1 (mPGES-1), vascular endothelial growth factor (VEGF), C-X-C chemokine receptor type 4 (CXCR4), matrix metalloproteinase-2 (MMP-2), MMP-9 and hypoxia-inducible factor-1 (HIF-1) were examined by quantitative real-time PCR. Apoptosis was evaluated by the proportion of sub-G1 cells. Prostaglandin E2 (PGE2) level and caspase 3 activity were determined by ELISA assay. Tube formation potential and HT-29 cells migration were assessed using three-dimensional vessel formation assay and scratch test.
RESULTS: B. serrata extract considerably decreased the expression of mPGES-1, VEGF, CXCR4, MMP-2, MMP-9 and HIF-1. The caspase 3 activity and percent of cells in sub-G1 phase were increased by B. serrata extract. Cell viability, PGE2 generation, in vitro tube formation and cell migration were decreased significantly in B. serrata-treated HT-29 compared to the control group.
CONCLUSION: Our findings suggest that B. serrata extract inhibits proliferation, angiogenesis and migration and induces apoptosis in HT-29 cells by inhibiting of mPGES-1 and decreasing the PGE2 level and its downstream targets.
Prostaglandins Other Lipid Mediat. 2017 Jul;131():1-8.
PMID: 28549801 [PubMed - indexed for MEDLINE]
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| 90. |
P-gp modulatory acetyl-11-keto-β-boswellic acid based nanoemulsified carrier system for augmented oral chemotherapy of docetaxel.
Pandey G, Mittapelly N, Valicherla GR, Shukla RP, Sharma S, Banala VT, Urandur S, Jajoriya AK, Mitra K, Mishra DP, Gayen JR, Mishra PR
In spite of being a very potent and promising drug against many types of cancer, docetaxel suffers the disadvantage of low solubility and poor bioavailability rendering it unsuitable for oral administration. Also, the available marketed formulation for intravenous administration has its inherent drawbacks owing to the presence of polysorbate 80. Here, we exploited the anticancer and P-gp inhibitory potential of naturally occurring frankincense oil to fabricate a stable docetaxel loaded nanoemulsified carrier system for oral delivery. The nanoemulsion possessing desirable particle size (122±12nm), polydispersity (0.086±0.007) and zeta potential (-29.8±2.1mV) was stable against all type of physical stresses and simulated physiological conditions tested. The formulation showed higher uptake in Caco-2 cells and inhibited P-gp transporter significantly (P<0.05). In MDA-MB-231 cells, it showed less IC, arrested cells in G2-M phase and exhibited higher degree of apoptosis than marketed formulation Taxotere. The 182.58±4.16% increment in relative oral bioavailability led to higher in vivo anti-proliferative activity manifesting 19% more inhibition than Taxotere. Conclusively, it is revealed that the developed nanoemulsion will be a propitious approach towards alternative docetaxel therapy.
Colloids Surf B Biointerfaces. 2017 Jul;155():276-286.
PMID: 28437753 [PubMed - indexed for MEDLINE]
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| 91. |
Boswellia serrata resin extract alleviates azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colon tumorigenesis.
Chou YC, Suh JH, Wang Y, Pahwa M, Badmaev V, Ho CT, Pan MH
SCOPE: Boswellia serrata (BS) resin is a popular dietary supplement for joint nourishment. In this study, we investigated the chemopreventive effects of dietary BS extract and its impact of gut microbiota on azoxymethane/dextran sulfate sodium (AOM/DSS)-induced colitis-associated colon cancer in mice.
METHODS AND RESULTS: Male ICR mice were injected with AOM and 2% DSS via drinking water. The mice were fed with 0.25 or 0.5% BS extract, and colonic tissue were collected at 15 weeks. The main effective components of BS supercritical CO extraction were analyzed by LC-MS/MS are boswellic acids. We found that treatment with BS extract significantly reduce the colonic tumor formation. Western blot and histological analysis revealed that dietary BS extract could markedly reduce the inflammation associated protein levels expression. Furthermore, BS extract reduced cell proliferation via inhibiting phosphorylation level of protein kinase B (Akt), glycogen synthase kinase 3β (GSK3β), and downregulation of cyclin D1. In addition, BS extract also altered the composition of gut microbiota by enhancing the proportion of Clostridiales and reducing the percentage of Bacteroidales.
CONCLUSION: In summary, BS extract decreased the protein levels of inflammative enzymes such as inducible nitric oxide synthase and cyclooxygenase-2 in colonic mucosa. It also mediated Akt/GSK3β/cyclin D1 signaling pathway and altered the composition of gut microbiota to alleviate tumor growth. Taken together, this study suggests that BS extract has great potential to suppress colon tumorigenesis.
Mol Nutr Food Res. 2017 Sep;61(9):.
PMID: 28245338 [PubMed - indexed for MEDLINE]
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| 92. |
Design and synthesis of novel 2-substituted 11-keto-boswellic acid heterocyclic derivatives as anti-prostate cancer agents with Pin1 inhibition ability.
Li K, Li L, Wang S, Li X, Ma T, Liu D, Jing Y, Zhao L
A series of novel acetyl-11-keto-β-boswellic acid (AKBA) derivatives with a different electron-withdrawing group on ring A and a nitrogen heterocycle at C-24 were designed and synthesized. These semi-synthetic compounds showed improved anti-proliferative activity against prostate cancer cells over AKBA. Compound 8f bearing 2-cyano-3,11-dioxo moiety and piperazine was the most potent to inhibit growth of prostate cancer PC-3 (IC = 0.04 μM) and LNCaP (IC = 0.27 μM) cell lines. 8f caused cell cycle arrest in G2/M and induced apoptosis. 8f decreased the protein levels of anti-apoptosis protein Mcl-1, c-FLIP and cell cycle regulating protein cyclin D1. 8f inhibited the activity of Pin1, a peptidyl-prolyl cis-trans isomerase to stabilize cyclin D1. 8f represented a compound with improved anti-proliferative effects for prostate cancer therapy working through new mechanisms.
Eur J Med Chem. 2017 Jan;126():910-919.
PMID: 27997878 [PubMed - indexed for MEDLINE]
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| 93. |
Ring A-modified Derivatives from the Natural Triterpene 3-O-acetyl-11-keto-β-Boswellic Acid and their Cytotoxic Activity.
Li T, Fan P, Ye Y, Luo Q, Lou H
BACKGROUND: Natural triterpene boswellic acids (BAs) have attracted much interest due to their anticancer activity, but more chemical modification is necessary to explore their pharmacological value. In addition to subtle functionalization, transformations that alter the triterpene skeleton are viewed as an alternative approach.
OBJECTIVE: In this study, transformations altering ring A of 3-O-acetyl-11-keto-β-boswellic acid (AKBA) were performed to obtain A-lactone, A-lactam, A-seco and A-contracted derivatives.
METHOD: Thirty-two new derivatives were synthesized, and their structures were confirmed by NMR and MS. Their anticancer activity against human cancer cell lines K562, PC3, A549 and HL60 was screened.
RESULTS: Biological evaluation indicated that the ring A cleavage or contraction transformations themselves did not significantly enhance the cytotoxic activity, but most of the derivatives based on these ring A-modified skeletons exhibited good cytotoxic activity. Significantly improved cytotoxicity was discovered for the esterified analogues of the A-lactone and A-lactam series and the amidated analogues of the A-seco and ring A contracted series, especially those bearing two nitrogen-containing substituents. Among them, compounds 6a, 11b, 12k and 18e showed strong cytotoxic activity, with IC50 values of 5.0~3.5 μM against K562 cells, almost ninefold stronger than that of AKBA. Further study proposed that the antiproliferative activities of 6a, 11b, 12k and 18e may be due to apoptosis induction.
CONCLUSION: The transformations of the ring A skeleton of AKBA provide new platforms to discover anticancer candidates.
Anticancer Agents Med Chem. 2017;17(8):1153-1167.
PMID: 27928954 [PubMed - indexed for MEDLINE]
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| 94. |
Interplay between cell cycle and autophagy induced by boswellic acid analog.
Pathania AS, Guru SK, Kumar S, Kumar A, Ahmad M, Bhushan S, Sharma PR, Mahajan P, Shah BA, Sharma S, Nargotra A, Vishwakarma R, Korkaya H, Malik F
In this study, we investigated the role of autophagy induced by boswellic acid analog BA145 on cell cycle progression in pancreatic cancer cells. BA145 induced robust autophagy in pancreatic cancer cell line PANC-1 and exhibited cell proliferation inhibition by inducing cells to undergo G2/M arrest. Inhibition of G2/M progression was associated with decreased expression of cyclin A, cyclin B, cyclin E, cdc2, cdc25c and CDK-1. Pre-treatment of cells with autophagy inhibitors or silencing the expression of key autophagy genes abrogated BA145 induced G2/M arrest and downregulation of cell cycle regulatory proteins. It was further observed that BA145 induced autophagy by targeting mTOR kinase (IC 1 μM), leading to reduced expression of p-mTOR, p-p70S6K (T389), p-4EBP (T37/46) and p-S6 (S240/244). Notably, inhibition of mTOR signalling by BA145 was followed by attendant activation of AKT and its membrane translocation. Inhibition of Akt through pharmacological inhibitors or siRNAs enhanced BA145 mediated autophagy, G2/M arrest and reduced expression of G2/M regulators. Further studies revealed that BA145 arbitrated inhibition of mTOR led to the activation of Akt through IGFR/PI3k/Akt feedback loop. Intervention in IGFR/PI3k/Akt loop further depreciated Akt phosphorylation and its membrane translocation that culminates in augmented autophagy with concomitant G2/M arrest and cell death.
Sci Rep. 2016 Sep;6():33146.
PMID: 27680387 [PubMed - as supplied by publisher]
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| 95. |
Chemical composition and biological activities of extracts and essential oil of Boswellia dalzielii leaves.
Kohoude MJ, Gbaguidi F, Agbani P, Ayedoun MA, Cazaux S, Bouajila J
CONTEXT: Boswellia dalzielii Hutch. (Burseraceae) is an aromatic plant. The leaves are used for beverage flavouring.
OBJECTIVE: This study investigates the chemical composition and biological activities of various extracts.
MATERIALS AND METHODS: The essential oil was prepared via hydrodistillation. Identification and quantification were realized via GC-MS and GC-FID. Consecutive extractions (cyclohexane, dichloromethane, ethyl acetate and methanol) were carried out and various chemical groups (phenolics, flavonoids, tannins, antocyanins and sugar) were quantified. The volatile compounds of organic extracts were identified before and after derivatization. Antioxidant, antihyperuricemia, anti-Alzheimer, anti-inflammatory and anticancer activities were evaluated.
RESULTS: In the essential oil, 50 compounds were identified, including 3-carene (27.72%) and α-pinene (15.18%). 2,5-Dihydroxy acetophenone and β-d-xylopyranose were identified in the methanol extract. Higher phenolic (315.97 g GAE/kg dry mass) and flavonoid (37.19 g QE/kg dry mass) contents were observed in the methanol extract. The methanol extract has presented remarkable IC=6.10 mg/L for antiDPPH, 35.10 mg/L for antixanthine oxidase and 28.01 mg/L for anti-5-lipoxygenase. For acetylcholinesterase inhibition, the best IC (76.20 and 67.10 mg/L) were observed, respectively, with an ethyl acetate extract and the essential oil. At 50 mg/L, the dichloromethane extract inhibited OVCAR-3 cell lines by 65.10%, while cyclohexane extract inhibited IGROV-1 cell lines by 92.60%.
DISCUSSION AND CONCLUSION: Biological activities were fully correlated with the chemical groups of the extracts. The ethyl acetate and methanol extracts could be considered as potential alternatives for use in dietary supplements for the prevention or treatment of diseases because of these extracts natural antioxidant, antihyperuricemic and anti-inflammatory activities.
Pharm Biol. 2017 Dec;55(1):33-42.
PMID: 27650786 [PubMed - indexed for MEDLINE]
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| 96. |
Therapeutic potential of boswellic acids: a patent review (1990-2015).
Hussain H, Al-Harrasi A, Csuk R, Shamraiz U, Green IR, Ahmed I, Khan IA, Ali Z
Boswellic acids (BAs), a group of pentacyclic triterpenoids, have demonstrated very interesting biological properties that resulted in a number of protocols being developed for their synthesis. During the last twenty-five years (1990-2015), numerous BAs have been prepared. Both natural BAs and their synthetic derivatives can be used to treat various cancers as well as inflammatory diseases. Areas covered: This review covers patents on therapeutic activities of natural BAs and their synthetic derivatives published in last twenty-five years (1990-2015). Only BA patents to treat cancer and inflammation are available. A discussion about structure-activity relationships (SAR) of these analogs is also included. Expert opinion: BAs possess excellent anticancer and anti-inflammatory properties. A large number of BAs and their analogues have been prepared through modification at the C-OH and C-COH functional groups. Most importantly, the C-24 amide and amino derivatives demonstrated increased anticancer and anti-inflammatory activity compared with other BA derivatives. Furthermore, BAs have the potential to form conjugates with other anticancer drugs that will synergistically enhance their anticancer effects; and we believe that in order to get lead compounds, there needs to be a greater focus on the synthesis of halo derivatives of BAs.
Expert Opin Ther Pat. 2017 Jan;27(1):81-90.
PMID: 27646163 [PubMed - indexed for MEDLINE]
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| 97. |
Role of angiogenic factors of herbal origin in regulation of molecular pathways that control tumor angiogenesis.
Kumar M, Dhatwalia SK, Dhawan DK
The formation of blood capillaries to sustain development and growth of new tissues is referred to as angiogenesis. Angiogenesis is pivotal in both carcinogenesis and metastasis since capillaries are the sole source of supplying nutrients and oxygen to the proliferating tumor cells; therefore, this dependency of tumor growth on angiogenesis challenges researchers to halt tumor growth by targeting angiogenesis with the help of either synthetic or natural inhibitors. Many synthetic inhibitors of angiogenesis have not only come into force but also resulted in some severe adverse effects. Natural compounds may effectively fit into this condition and possibly decrease the time of treatment. In the recent past, literature is replete with evidences advocating the usefulness of natural compounds that target multiple biochemical pathways. The additional advantage of natural compounds is that their active principles interact with one another and work synergistically to give more meaningful and reliable effects than individual principle. Hence, if we are somehow able to combine more than two natural compounds, then it may be possible to enhance their potential by many folds, which shall prove to be very effective in combating tumor angiogenesis. This review shall discuss the concept of angiogenesis, molecular pathways, and angiogenic inhibitors and their specific targets and potential of natural compounds to greatly enhance the current knowledge of angiogenesis-inhibiting factors.
Tumour Biol. 2016 Nov;37(11):14341-14354.
PMID: 27614685 [PubMed - indexed for MEDLINE]
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| 98. |
Chemical composition, antiproliferative, antioxidant and antibacterial activities of essential oils from aromatic plants growing in Sudan.
Yagi S, Babiker R, Tzanova T, Schohn H
OBJECTIVE: To explore the potential of essential oil, as therapeutic molecule source, from olibanum of Boswellia papyrifera (Burseraceae), leafy stems of Cymbopogon schoenanthus (Poaceae) and Croton zambesicus (Euphorbiaceae) and rhizome of Cyperus rotundus (Cyperaceae) found in Sudan. Respective essential oil was evaluated for anti-proliferative, antibacterial and antioxidant activity.
METHODS: Essential oils were extracted by hydrodistillation and then analysed by gas chromatography coupled to mass spectrometry (GC-MS). Anti-proliferative activity was determined against human cell lines (MCF7 and MDA-MB231, HT29 and HCT116) by the thiazolyl blue tetrazolium bromide (MTT) procedure. Antioxidant activity was evaluated by diphenyl 2 pycril hydrazil (DPPH) assay. Antibacterial activity was determined against two Gram-positive and two Gram-negative bacteria by microdilution method.
RESULTS: The essential oil from olibanum of Boswellia papyrifera contained mainly alcohol and ester derivatives (46.82%) while monoterpenes (69.84%) dominated in Corton zambesicus oil. Sesquiterpenes were the most highly represented classes of terpene derivatives in Cyperus schoenanthus (71.59%) and Cyperus rotundus (44.26%). Oil of Cymbopogon schoenanthus revealed the best anti-proliferative activity against HCT116 cell line with IC50 value at (19.1 ± 2.0) μg/mL. Oil of Croton zambesicus showed the best antioxidant activity [EC50 (4.20 ± 0.19) mg/mL]. All oils showed good antibacterial activity against Escherichia coli, Bacillus subtilis and Staphylococcus aureus with minimum inhibitory concentration (MIC) value ranged from 16 to 250 μg/mL.
CONCLUSIONS: The results suggest that the essential oils of these plants could be used as a source of natural anti-proliferative, antioxidant and antibacterial agents.
Asian Pac J Trop Med. 2016 Aug;9(8):763-70.
PMID: 27569885 [PubMed - as supplied by publisher]
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| 99. |
Reversal of the multidrug resistance of human ileocecal adenocarcinoma cells by acetyl-11-keto-β-boswellic acid via downregulation of P-glycoprotein signals.
Xue X, Chen F, Liu A, Sun D, Wu J, Kong F, Luan Y, Qu X, Wang R
Multidrug resistance (MDR) represents a clinical obstacle to cancer chemotherapy since it causes cancer recurrence and metastasis. Acetyl-11-keto-β-boswellic acid (AKBA), an active ingredient derived from the plant Boswellia serrata, has been found to inhibit the growth of a wide variety of tumor cells, including glioma, colorectal cancer, leukemia, human melanoma, hepatocellular carcinoma, and prostate cancer cells. However, the actions of AKBA in multidrug-resistant cancer cells have not been fully elucidated. The current study examined the reversal of MDR by AKBA in a human ileocecal adenocarcinoma cell line with vincristine-induced resistance, HCT-8/VCR. A 3-[4, 5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide (MTT) assay indicated that cytotoxicity increased drastically and the IC50 of VCR in HCT-8/VCR cells decreased in the presence of AKBA. AKBA had a maximum "fold reversal" of MDR (FR) of 9.19-fold. In addition, HCT-8/VCR cells treated with AKBA and VCR exhibited a higher percentage of apoptotic tumor cells according to flow cytometry. The reversal of MDR by AKBA was evident in an intracellular increase in Rhodamine (Rh123), indicating that the activity of P-glycoprotein (P-gp) was blocked. Furthermore, AKBA inhibited the expression of P-gp and decreased levels of expression of multidrug resistance gene 1 in HCT-8/VCR cells. The current results indicated that AKBA might be a potential agent to reverse MDR in human ileocecal adenocarcinoma.
Biosci Trends. 2016 Nov;10(5):392-399.
PMID: 27545217 [PubMed - indexed for MEDLINE]
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| 100. |
Improved efficacy of cisplatin in combination with a nano-formulation of pentacyclic triterpenediol.
Alam N, Qayum A, Kumar A, Khare V, Sharma PR, Andotra SS, Singh SK, Koul S, Gupta PN
Cisplatin is widely used for the treatment of various cancers including cervical, ovarian, lung and head and neck, however, its clinical success is limited owing to the dose-dependent adverse effects, mainly nephrotoxicity and neurotoxicity. In order to address this limitation, the present study was undertaken to investigate growth inhibitory effect of cisplatin in combination with a triterpenediol (3a, 24-dihydroxyurs-12-ene and 3a, 24-dihydroxyolean-12-ene, TPD) on human ovarian cancer cell line. Poly(dl-lactic-co-glycolic) acid nanoparticles loaded with TPD (TPD-PLGA-NPs) were successfully developed by emulsion solvent evaporation method. The TPD-PLGA-NPs were characterized for size distribution and zeta potential which was in order of 152.56±3.01nm and -17.36±0.37mV respectively. The morphological evaluation was carried out by transmission electron microscopy and the formulation was also characterized using Fourier transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC). The drug loading of the optimized formulation was 51.03±1.52μg/mg and the formulation exhibited sustained drug release profile. The in vitro cellular uptake study of coumarin-6 loaded PLGA nanoparticles in OVCAR-5 cells demonstrated a time dependent increase in uptake efficiency. Further, growth inhibitory effect of cisplatin was investigated in combination with TPD-PLGA-NPs. The combination index (CI) was <1, indicating a synergistic interaction. Further, at 75% of cell growth inhibition (ED75) the dose of cisplatin was reduced to 3.8 folds using this combination. The results indicated the potential of cisplatin and TPD-PLGA-NPs combination in order to reduce to dose limiting toxicities of the former.
Mater Sci Eng C Mater Biol Appl. 2016 Nov;68():109-116.
PMID: 27524002 [PubMed - indexed for MEDLINE]
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| 101. |
β-Boswellic acid, a bioactive substance used in food supplements, inhibits protein synthesis by targeting the ribosomal machinery.
Casapullo A, Cassiano C, Capolupo A, Del Gaudio F, Esposito R, Tosco A, Riccio R, Monti MC
The Boswellia gum resin extracts have been used in traditional medicines because of their remarkable anti-inflammatory properties. Nowadays, these extracts are on the market as food supplements. β-Boswellic acid (βBA) is one of the main pentacyclic triterpene components, among the family of BAs, of the Boswellia gum resins. BAs have been broadly studied and are well known for their wide anti-inflammatory and potential anticancer properties. In this paper, a mass spectrometry-based chemoproteomic approach has been applied to characterize the whole βBA interacting profile. Among the large numbers of proteins fished out, proteasome, 14-3-3 and some ribosomal proteins were considered the most interesting targets strictly connected to the modulation of the cancer progression. In particular, because of their recent assessment as innovative chemotherapeutic targets, the ribosomal proteins were considered the most attractive βBA partners, and the biological role of their interaction with the natural compound has been evaluated. Copyright © 2016 John Wiley & Sons, Ltd.
J Mass Spectrom. 2016 Sep;51(9):821-7.
PMID: 27460774 [PubMed - indexed for MEDLINE]
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| 102. |
Boswellic acid disables signal transduction of IL-6-STAT-3 in Ehrlich ascites tumor bearing irradiated mice.
Moustafa EM, Thabet NM, Azab KS
Boswellic acid (BA) is known for its ability to trigger apoptosis as well as to inhibit angiogenesis in tumor tissue. In this study, we investigated the effect of BA on the IL-6-STAT-3 signalling pathway in irradiated mice bearing solid tumors of Ehrlich ascites carcinoma (EAC). For this, we administered BA (25 mg·(kg body mass)(-1)·day(-1), by intraperitoneal injection) to mice with EAC, and then exposed them to 4 Gy of gamma radiation. Data analyses of the results revealed a specific impact from BA on IL-6R mRNA and survivin mRNA in EACs and irradiated EAC-bearing mice. Also, significant improvements were observed in the protein expression of JAK-1, P-JAK-1, STAT-3, P-STAT-3, and caspase-3, as well as VEGF and IL-6 levels. We propose that BA interfered with IL-6-STAT-3 signal transduction, thereby preventing the activation of caspase-3 and subsequently triggering the process of apoptosis. However, the alternative angiogenesis pathway, which includes the over-expression of VEGF and which depends on IL-6-STAT-3 signalling, was inhibited by the action of BA. Thus, we recommend that therapeutic strategies for cancer should include treatment with BA.
Biochem Cell Biol. 2016 Aug;94(4):307-13.
PMID: 27458759 [PubMed - indexed for MEDLINE]
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| 103. |
Current state of phenolic and terpenoidal dietary factors and natural products as non-coding RNA/microRNA modulators for improved cancer therapy and prevention.
Biersack B
The epigenetic regulation of cancer cells by small non-coding RNA molecules, the microRNAs (miRNAs), has raised particular interest in the field of oncology. These miRNAs play crucial roles concerning pathogenic properties of cancer cells and the sensitivity of cancer cells towards anticancer drugs. Certain miRNAs are responsible for an enhanced activity of drugs, while others lead to the formation of tumor resistance. In addition, miRNAs regulate survival and proliferation of cancer cells, in particular of cancer stem-like cells (CSCs), that are especially drug-resistant and, thus, cause tumor relapse in many cases. Various small molecule compounds were discovered that target miRNAs that are known to modulate tumor aggressiveness and drug resistance. This review comprises the effects of naturally occurring small molecules (phenolic compounds and terpenoids) on miRNAs involved in cancer diseases.
Noncoding RNA Res. 2016 Oct;1(1):12-34.
PMID: 30159408 [PubMed - as supplied by publisher]
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| 104. |
Pharmacological evidences for cytotoxic and antitumor properties of Boswellic acids from Boswellia serrata.
Khan MA, Ali R, Parveen R, Najmi AK, Ahmad S
ETHNOPHARMACOLOGICAL RELEVANCE: Increasing research on traditional herbal medicines and their phytoconstituents has recognized their usefulness in complementary as adjuvant to chemotherapy in various types of cancers. The oleo-gum resin of Boswellia serrata tree is one such folk medicine, which has been traditionally used for religious, cosmetic as well as medical purposes since ages. The oleo-gum resin of the plant has been used in traditional medicine to treat variety of conditions including inflammatory diseases like arthritis, asthma, chronic pain, bowel conditions and many other diseases. This review presents an overview of scientific studies on cytotoxic and antitumor properties of B. serrata and its constituents.
MATERIALS AND METHODS: Literature search was carried out for activities of B. serrata and various isolated boswellic acids such as β-boswellic acid, 11-keto-β-boswellic acid and acetyl-11-keto-β-boswellic acid reported in various cancer types in vitro as well as in vivo.
RESULTS: The triterpenoidal fraction of B. serrata (containing boswellic acids) is responsible for the cytotoxic and antitumor properties. Among the screened compounds, 3-O-acetyl-11-keto-β-boswellic acid has been found to be most promising cytotoxic molecule. The cytotoxic and antitumor effects are mainly due to induction of apoptosis through caspase activation, increased Bax expression, NF-κB down regulation and induction of poly (ADP)-ribose polymerase (PARP) cleavage.
CONCLUSIONS: Boswellic acids appear to be promising candidates for anticancer drug development in future. However, further in vivo studies are needed. Studies in combination with clinically used anticancer drugs and QSAR studies on individual boswellic acid also need to be carried out.
J Ethnopharmacol. 2016 Sep;191():315-323.
PMID: 27346540 [PubMed - indexed for MEDLINE]
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| 105. |
Boswellic acid activity against glioblastoma stem-like cells.
Schneider H, Weller M
Boswellic acids (BAs) have long been considered as useful adjunct pharmacological agents for the treatment of patients with malignant brain tumors, notably glioblastoma. Two principal modes of action associated with BAs have been postulated: i) Anti-inflammatory properties, which are useful for containing edema formation, and ii) intrinsic antitumor cell properties, with a hitherto ill-defined mode of action. The present study assessed the effects of various BA derivatives on the viability and clonogenicity of a panel of nine long-term glioma cell lines and five glioma-initiating cell lines, studied cell cycle progression and the mode of cell death induction, and explored potential synergy with temozolomide (TMZ) or irradiation. BA induced the concentration-dependent loss of viability and clonogenicity that was independent of tumor protein 53 status and O6-methylguanine DNA methyltransferase expression. The treatment of glioma cells with BA resulted in cell death induction, prior to or upon S phase entry, and exhibited features of apoptotic cell death. Synergy with irradiation or TMZ was detected at certain concentrations; however, the inhibitory effects were mostly additive, and never antagonistic. While the intrinsic cytotoxic properties of BA at low micromolecular concentrations were confirmed and the potential synergy with irradiation and TMZ was identified, the proximate pharmacodynamic target of BA remains to be identified.
Oncol Lett. 2016 Jun;11(6):4187-4192.
PMID: 27313764 [PubMed - as supplied by publisher]
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| 106. |
Frankincense--therapeutic properties.
Al-Yasiry AR, Kiczorowska B
Recently, increasing interest in natural dietary and therapeutic preparations used as dietary supplements has been observed. One of them is frankincense. This traditional medicine of the East is believed to have anti-inflammatory, expectorant, antiseptic, and even anxiolytic and anti-neurotic effects. The present study aims to verify the reported therapeutic properties of Boswellia resin and describe its chemical composition based on available scientific studies. The main component of frankincense is oil (60%). It contains mono- (13%) and diterpenes (40%) as well as ethyl acetate (21.4%), octyl acetate (13.4%) and methylanisole (7.6%). The highest biological activity among terpenes is characteristic of 11-keto-ß-acetyl-beta-boswellic acid, acetyl-11-keto-ß-boswellic acid and acetyl-α-boswellic acid. Contemporary studies have shown that resin indeed has an analgesic, tranquilising and anti-bacterial effects. From the point of view of therapeutic properties, extracts from Boswellia serrata and Boswellia carterii are reported to be particularly useful. They reduce inflammatory conditions in the course of rheumatism by inhibiting leukocyte elastase and degrading glycosaminoglycans. Boswellia preparations inhibit 5-lipoxygenase and prevent the release of leukotrienes, thus having an anti-inflammatory effect in ulcerative colitis, irritable bowel syndrome, bronchitis and sinusitis. Inhalation and consumption of Boswellia olibanum reduces the risk of asthma. In addition, boswellic acids have an antiproliferative effect on tumours. They inhibit proliferation of tumour cells of the leukaemia and glioblastoma subset. They have an anti-tumour effect since they inhibit topoisomerase I and II-alpha and stimulate programmed cell death (apoptosis).
Postepy Hig Med Dosw (Online). 2016 Jan;70():380-91.
PMID: 27117114 [PubMed - indexed for MEDLINE]
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| 107. |
The potential role of boswellic acids in cancer prevention and treatment.
Roy NK, Deka A, Bordoloi D, Mishra S, Kumar AP, Sethi G, Kunnumakkara AB
Despite the extensive research carried out in the field of cancer therapeutics, cancer is one of the most dreadful diseases in the world with no definitive treatment to date. The key attributes responsible for this are the various limiting factors associated with conventional chemotherapeutics that primarily include adverse side-effects and development of chemoresistance. Hence, there is an utter need to find compounds that are highly safe and efficacious for the prevention and treatment of cancer. Boswellic acid, a group of pentacyclic compounds, seems to be promising enough due to its inherent anti-cancerous properties. Considering this perspective, the present review highlights the established studies related to the anti-cancer potential of boswellic acid against different cancer types. The molecular mechanisms underlying the targets of boswellic acid that are accountable for its potent anti-cancer effect are also discussed. Overall, this review projects the pieces of evidence that reveal the potential of boswellic acid as a suitable candidate that can be appropriately developed and designed into a promising anti-cancer drug.
Cancer Lett. 2016 Jul;377(1):74-86.
PMID: 27091399 [PubMed - indexed for MEDLINE]
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| 108. |
Use of Boswellia-based cream for prevention of adjuvant radiotherapy skin damage in mammary carcinoma.
Bonucci M, Fioranelli M, Roccia MG, Di Nardo V, Carolina JA, Lotti T
Dermatol Ther. 2016 Nov;29(6):393.
PMID: 27003094 [PubMed - indexed for MEDLINE]
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| 109. |
Synthesis of β-boswellic acid derivatives as cytotoxic and apoptotic agents.
Kumar A, Qayum A, Sharma PR, Singh SK, Shah BA
A series of β-boswellic acid derivatives were synthesized and evaluated for anticancer activity. One of the lead analog 4f displayed significant anticancer activity against a panel of cancer cells as well as substantially inhibited colony formation in HCT-116 cells. Furthermore, 4f was found to be a potent inducer of apoptosis confirmed by loss of mitochondrial membrane potential, DAPI staining, Western blotting and ROS generation.
Bioorg Med Chem Lett. 2016 Jan;26(1):76-81.
PMID: 26608550 [PubMed - indexed for MEDLINE]
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| 110. |
Phytochemical Analysis and Anti-cancer Investigation of Boswellia serrata Bioactive Constituents In Vitro.
Ahmed HH, Abd-Rabou AA, Hassan AZ, Kotob SE
Cancer is a major health obstacle around the world, with hepatocellular carcinoma (HCC) and colorectal cancer (CRC) as major causes of morbidity and mortality. Nowadays, there isgrowing interest in the therapeutic use of natural products for HCC and CRC, owing to the anticancer activity of their bioactive constituents. Boswellia serrata oleo gum resin has long been used in Ayurvedic and traditional Chinese medicine to alleviate a variety of health problems such as inflammatory and arthritic diseases. The current study aimed to identify and explore the in vitro anticancer effect of B. Serrata bioactive constituents on HepG2 and HCT 116 cell lines. Phytochemical analysis of volatile oils of B. Serrata oleo gum resin was carried out using gas chromatography- mass spectrometry (GC/MS). Oleo-gum-resin of B. Serrata was then successively extracted with petroleum ether (extract 1) and methanol (extract 2). Gas-liquid chromatography (GLC) analysis of the lipoidal matter was also performed. In addition, a methanol extract of B. Serrata oleo gum resin was phytochemically studied using column chromatography (CC) and thin layer chromatography (TLC) to obtain four fractions (I, II, III and IV). Sephadex columns were used to isolate β-boswellic acid and identification of the pure compound was done using UV, mass spectra, 1H NMR and 13C NMR analysis. Total extracts, fractions and volatile oils of B. Serrata oleo-gum resin were subsequently applied to HCC cells (HepG2 cell line) and CRC cells (HCT 116 cell line) to assess their cytotoxic effects. GLC analysis of the lipoidal matter resulted in identification of tricosane (75.32%) as a major compound with the presence of cholesterol, stigmasterol and β-sitosterol. Twenty two fatty acids were identified of which saturated fatty acids represented 25.6% and unsaturated fatty acids 74.4% of the total saponifiable fraction. GC/MS analysis of three chromatographic fractions (I,II and III) of B. Serrata oleo gum resin revealed the presence of pent-2-ene-1,4-dione, 2-methyl- levulinic acid methyl ester, 3,5- dimethyl- 1- hexane, methyl-1-methylpentadecanoate, 1,1- dimethoxy cyclohexane, 1-methoxy-4-(1-propenyl)benzene and 17a-hydroxy-17a-cyano, preg-4-en-3-one. GC/MS analysis of volatile oils of B. Serrata oleo gum resin revealed the presence of sabinene (19.11%), terpinen-4-ol (14.64%) and terpinyl acetate (13.01%) as major constituents. The anti-cancer effect of two extracts (1 and 2) and four fractions (I, II, III and IV) as well as volatile oils of B. Serrata oleo gum resin on HepG2 and HCT 116 cell lines was investigated using SRB assay. Regarding HepG2 cell line, extracts 1 and 2 elicited the most pronounced cytotoxic activity with IC50 values equal 1.58 and 5.82 μg/mL at 48 h, respectively which were comparable to doxorubicin with an IC50 equal 4.68 μg/mL at 48 h. With respect to HCT 116 cells, extracts 1 and 2 exhibited the most obvious cytotoxic effect; with IC50 values equal 0.12 and 6.59 μg/mL at 48 h, respectively which were comparable to 5-fluorouracil with an IC50 equal 3.43 μg/ mL at 48 h. In conclusion, total extracts, fractions and volatile oils of B. Serrata oleo gum resin proved their usefulness as cytotoxic mediators against HepG2 and HCT 116 cell lines with different potentiality (extracts > fractions > volatile oil). In the two studied cell lines the cytotoxic acivity of each of extract 1 and 2 was comparable to doxorubicin and 5-fluorouracil, respectively. Extensive in vivo research is warranted to explore the precise molecular mechanisms of these bioactive natural products in cytotoxicity against HCC and CRC cells.
Asian Pac J Cancer Prev. 2015;16(16):7179-88.
PMID: 26514509 [PubMed - indexed for MEDLINE]
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| 111. |
Triggering of Suicidal Erythrocyte Death Following Boswellic Acid Exposure.
Calabrò S, Alzoubi K, Faggio C, Laufer S, Lang F
BACKGROUND/AIMS: The antinflammatory natural product boswellic acid is effective against cancer at least in part by inducing tumor cell apoptosis. Similar to apoptosis of nucleated cells erythrocytes may enter eryptosis, a suicidal death characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Stimulators of eryptosis include oxidative stress, increase of cytosolic Ca(2+)-activity ([Ca(2+)]i), energy depletion, ceramide formation and p38 kinase activation. The present study tested, whether and how boswellic acid induces eryptosis.
METHODS: Phosphatidylserine exposure at the cell surface was estimated from annexin V binding, cell volume from forward scatter, hemolysis from hemoglobin release, [Ca(2+)]i from Fluo3-fluorescence, ceramide abundance utilizing specific antibodies, reactive oxygen species (ROS) from 2',7'-dichlorodihydrofuorescein diacetate (DCFDA) fluorescence, and cytosolic ATP concentration utilizing a luciferin-luciferase assay kit.
RESULTS: A 24 hours exposure of human erythrocytes to boswellic acid (5 µg/ml) significantly increased the percentage of annexin-V-binding cells (to 9.3 ± 0.9 %) and significantly decreased forward scatter. Boswellic acid did not significantly modify [Ca(2+)]i, cytosolic ATP, ROS, or ceramide abundance. The effect of boswellic acid on annexin-V-binding was significantly blunted, but not abolished by p38 kinase inhibitors skepinone (2 µM) and SB203580 (2 µM).
CONCLUSIONS: Boswellic acid stimulates cell shrinkage and phospholipid scrambling of the erythrocyte cell membrane, an effect in part dependent on p38 protein kinase activity.
Cell Physiol Biochem. 2015;37(1):131-42.
PMID: 26303375 [PubMed - indexed for MEDLINE]
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| 112. |
Combination of Anti-Diabetic Drug Metformin and Boswellic Acid Nanoparticles: A Novel Strategy for Pancreatic Cancer Therapy.
Snima KS, Nair RS, Nair SV, Kamath CR, Lakshmanan VK
Pancreatic cancer has an infaust prognosis and is the fourth common cause of cancer related death in India. It is highly resistant to conventional treatment modalities such as chemotherapy, radiation therapy and surgery. The association of pancreatic cancer and diabetes mellitus is explored in our study. Pancreatic cancer is more likely to occur in people who have diabetes than people devoid of it, which is supported by the observation that hyperglycaemia occurs at an early stage of pancreatic cancer and is indeed a risk factor. In the present study, we have demonstrated a synergistic relationship between metformin and boswellic acid nanoparticles with varying doses of boswellic acid nanoparticles and constant metformin (20 mM). The effect revealed increased synergism between metformin and boswellic acid nanoparticles through the inhibition of cell proliferation with an effect of 80% for the combination with 0.3 mg/mL and 0.4 mg/mL and a constant concentration of metformin. We examined the effect of combination on cell migration which revealed time dependent inhibitory effect on pancreatic cell line (MiaPaCa-2). Also, we found that the combinatorial approach significantly decreased colony formation and exhibited high rate of induction of apoptosis through DNA fragmentation in pancreatic cancer cells. In-vitro hemolysis confirmed the hemocompatibility of the combination therapy with metformin and boswellic acid nanoparticles. Flow cytometry based apoptosis assay and Caspase mediated apoptosis proved apoptosis mediated cell death. Further, the cells were analysed with mitochondrial membrane potential kit which revealed depolarization of mitochondrial membrane potential due to apoptosis after treatment with drug combination. Hence, the combination approach proved to be a promising therapy towards pancreatic cancer.
J Biomed Nanotechnol. 2015 Jan;11(1):93-104.
PMID: 26301303 [PubMed - indexed for MEDLINE]
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| 113. |
Boswellic acids synergize antitumor activity and protect against the cardiotoxicity of doxorubicin in mice bearing Ehrlich's carcinoma.
Ali SA, Zaitone SA, Moustafa YM
This study aimed to test whether boswellic acids add to the antitumor effects of doxorubicin against solid tumors of Ehrlich's ascites carcinoma (EAC) grown in mice, and to investigate the protective effects of boswellic acids against doxorubicin-induced cardiotoxicity. Sixty-four female Swiss albino mice bearing EAC solid tumors were distributed among 8 groups as follows: group 1, EAC control group; group 2, doxorubicin treatment group [mice were injected with doxorubicin (6 mg·(kg body mass)(-1)·week(-1)) for 3 weeks]; groups 3-5, these mice were treated with boswellic acids (125, 250, or 500 mg·kg(-1)·day(-1)), respectively; groups 6-8, these mice were treated with a combination of doxorubicin and boswellic acids (125, 250, or 500 mg·kg(-1)·day(-1)), respectively, for 3 weeks. The results indicated that boswellic acids synergized the antitumor activity of doxorubicin. Doxorubicin-treated mice showed elevated serum activities of lactate dehydrogenase and creatine kinase isoenzyme MB as well as cardiac malondialdehyde. Further, decreases in cardiac levels of reduced glutathione, superoxide dismutase, and catalase activities were observed. These effects were accompanied by an increase in cardiac expression of caspase 3. Thus, treatment with boswellic acids attenuated doxorubicin-evoked disturbances in the above-mentioned parameters, highlighting antioxidant and antiapoptotic activities. Therefore, boswellic acids could be potential candidates for ameliorating the cardiotoxicity of doxorubicin.
Can J Physiol Pharmacol. 2015 Aug;93(8):695-708.
PMID: 26230640 [PubMed - indexed for MEDLINE]
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| 114. |
11-Keto-boswellic acid derived amides and monodesmosidic saponins induce apoptosis in breast and cervical cancers cells.
Csuk R, Barthel-Niesen A, Barthel A, Schäfer R, Al-Harrasi A
Beta-boswellic acids are considered the main bioactive components of frankincense. Their potential to act as cytotoxic agents, as well as that of their derivatives remained unexploited so far. In this study we were able to prepare derivatives of 11-keto-β-boswellic acid (KBA) that showed lower IC50 values as determined by a sulphorhodamine B (SRB) assay using several different human tumour cell lines. Monodesmosidic saponins of KBA are as cytotoxic as 3-acetyl-KBA. The presence of a free hydroxyl group at position C-3 seems to lower cytotoxicity while the presence of an amide function at C-24 improves cytotoxicity. The most active compound of this series gave IC50 values as low as 4.5 μM. Cell death proceeded mainly via apoptosis.
Eur J Med Chem. 2015 Jul;100():98-105.
PMID: 26073487 [PubMed - indexed for MEDLINE]
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| 115. |
Synthesis and structure-activity relationships of boswellic acid derivatives as potent VEGFR-2 inhibitors.
Shen S, Xu X, Liu Z, Liu J, Hu L
A series of AKBA derivatives were synthesized, and evaluated as potent VEGFR-2 inhibitors. The initial biological evaluation indicated that the introduction of C-24 amide group or a heterocycle at C-2,3 position effectively improved the potency. Further structure-activity relationship analysis showed that amide (7, 23, 25, and 26) and heterocycle (19, 34, and 36) substituted AKBA derivatives displayed more potential anti-proliferation activities than AKBA (1) on HUVECs that express high levels of VEGFR-2. Among all tested compounds, compounds 7 and 19 exhibited the best potency (IC₅₀: 2.36 and 2.13 μM) and obvious inhibitory activities with VEGFR-2 inhibition rates of 96% and 94% at 50 μM, respectively.
Bioorg Med Chem. 2015 May;23(9):1982-93.
PMID: 25819335 [PubMed - indexed for MEDLINE]
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| 116. |
Novel Evidence for Curcumin and Boswellic Acid-Induced Chemoprevention through Regulation of miR-34a and miR-27a in Colorectal Cancer.
Toden S, Okugawa Y, Buhrmann C, Nattamai D, Anguiano E, Baldwin N, Shakibaei M, Boland CR, Goel A
Colorectal cancer is one of the most common causes of cancer-associated mortality worldwide, but it is truly a preventable disease. Both curcumin and boswellic acids are well-established dietary botanicals with potent antitumorigenic properties that have been shown to modulate multiple oncogenic pathways. Recent data suggest that the chemopreventive effects of these botanicals may, in part, be mediated through regulation of key cancer-related microRNAs (miRNA) and their downstream gene targets. Here, we investigated the antitumorigenic effects of curcumin and 3 acetyl-11-keto-β-boswellic acid (AKBA) on modulation of specific cancer-related miRNAs in colorectal cancer cells and validated their protective effects in vivo using a xenograft mouse model. Both curcumin and AKBA inhibited cellular proliferation, induced apoptosis and cell-cycle arrest in colorectal cancer cell lines, and these effects were significantly enhanced with combined treatment. Gene-expression arrays revealed that curcumin and AKBA regulated distinct cancer signaling pathways, including key cell-cycle regulatory genes. Combined bioinformatics and in silico analysis identified apoptosis, proliferation, and cell-cycle regulatory signaling pathways as key modulators of curcumin and AKBA-induced anticancer effects. We discovered that curcumin and AKBA induced upregulation of tumor-suppressive miR-34a and downregulation of miR-27a in colorectal cancer cells. Furthermore, we demonstrated in a mouse xenograft model that both curcumin and AKBA treatments suppressed tumor growth, which corresponded with alterations in the expression of miR-34a and miR-27a, consistent with our in vitro findings. Herein, we provide novel mechanistic evidence for the chemopreventive effects of curcumin and AKBA through regulation of specific miRNAs in colorectal cancer.
Cancer Prev Res (Phila). 2015 May;8(5):431-43.
PMID: 25712055 [PubMed - indexed for MEDLINE]
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| 117. |
Prediction of anticancer property of bowsellic acid derivatives by quantitative structure activity relationship analysis and molecular docking study.
Satpathy R, Guru RK, Behera R, Nayak B
CONTEXT: Boswellic acid consists of a series of pentacyclic triterpene molecules that are produced by the plant Boswellia serrata. The potential applications of Bowsellic acid for treatment of cancer have been focused here.
AIMS: To predict the property of the bowsellic acid derivatives as anticancer compounds by various computational approaches.
MATERIALS AND METHODS: In this work, all total 65 derivatives of bowsellic acids from the PubChem database were considered for the study. After energy minimization of the ligands various types of molecular descriptors were computed and corresponding two-dimensional quantitative structure activity relationship (QSAR) models were obtained by taking Andrews coefficient as the dependent variable.
STATISTICAL ANALYSIS USED: Different types of comparative analysis were used for QSAR study are multiple linear regression, partial least squares, support vector machines and artificial neural network.
RESULTS: From the study geometrical descriptors shows the highest correlation coefficient, which indicates the binding factor of the compound. To evaluate the anticancer property molecular docking study of six selected ligands based on Andrews affinity were performed with nuclear factor-kappa protein kinase (Protein Data Bank ID 4G3D), which is an established therapeutic target for cancers. Along with QSAR study and docking result, it was predicted that bowsellic acid can also be treated as a potential anticancer compound.
CONCLUSIONS: Along with QSAR study and docking result, it was predicted that bowsellic acid can also be treated as a potential anticancer compound.
J Pharm Bioallied Sci. 2015;7(1):21-5.
PMID: 25709332 [PubMed - as supplied by publisher]
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| 118. |
Synthesis and antitumor activity of ring A modified 11-keto-β-boswellic acid derivatives.
Csuk R, Niesen-Barthel A, Schäfer R, Barthel A, Al-Harrasi A
Beta-boswellic acids are interesting triterpenoic acids that show different biological activities. Their cytotoxic potential, as well as that of their derivates remained unexploited so far. In this study we were able to prepare derivatives of 11-keto-β-boswellic acid that showed lower IC50 values as determined by a sulphorhodamine B (SRB) assay using several different human tumour cell lines. Thus, the introduction of an amino group at position C-2 led to a significantly improved cytotoxic activity of amine 18. An apoptotic effect of compound 18 was determined using DNA laddering and trypan blue staining experiments.
Eur J Med Chem. 2015 Mar;92():700-11.
PMID: 25618017 [PubMed - indexed for MEDLINE]
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| 119. |
Retraction notice to "Acetyl-11-β-boswellic acid (AKBA)inhibits human gastric carcinoma growth through modulation of the Wnt/β-canetin signalin pathway" Biochimica et Biophysica Acta [1830 (6) 3604-3615].
Biochim Biophys Acta. 2015 Jan;1850(1):254.
PMID: 25610930 [PubMed - as supplied by publisher]
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| 120. |
Retraction notice to "Acetyl-11-keto-beta-boswellic acid (AKBA) prevents human colonic adenocarcinoma growth through modulation of multiple signaling pathways" Biochimica et Biophysica Acta [1830 (10) 4907-4916].
Biochim Biophys Acta. 2015 Jan;1850(1):253.
PMID: 25610929 [PubMed - as supplied by publisher]
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| 121. |
The anti-angiogenic and cytotoxic effects of the boswellic acid analog BA145 are potentiated by autophagy inhibitors.
Pathania AS, Wani ZA, Guru SK, Kumar S, Bhushan S, Korkaya H, Seals DF, Kumar A, Mondhe DM, Ahmed Z, Chandan BK, Malik F
BACKGROUND: While angiogenesis inhibitors represent a viable cancer therapy, there is preclinical and clinical data to suggest that many tumors develop resistance to such treatments. Moreover, previous studies have revealed a complex association between autophagy and angiogenesis, and their collective influence on tumorigenesis. Autophagy has been implicated in cytoprotection and tumor promotion, and as such may represent an alternative way of targeting apoptosis-resistant cancer cells. This study explored the anti-cancer agent and boswellic acid analog BA145 as an inducer of autophagy and angiogenesis-mediated cytoprotection of tumor cells.
METHODS: Flow cytometry, western blotting, and confocal microscopy were used to investigate the role of BA145 mediated autophagy. ELISA, microvessel sprouting, capillary structure formation, aortic ring and wound healing assays were performed to determine the relationship between BA145 triggered autophagy and angiogenesis. Flow cytometery, western blotting, and microscopy were employed to examine the mechanism of BA145 induced cell death and apoptosis. Live imaging and tumor volume analysis were carried out to evaluate the effect of BA145 triggered autophagy on mouse tumor xenografts.
RESULTS: BA145 induced autophagy in PC-3 cancer cells and HUVECs significantly impeded its negative regulation on cell proliferation, migration, invasion and tube formation. These effects of BA145 induced autophagy were observed under both normoxic and hypoxic conditions. However, inhibition of autophagy using either pharmacological inhibitors or RNA interference enhanced the BA145 mediated death of these cells. Similar observations were noticed with sunitinib, the anti-angiogenic properties of which were significantly enhanced during combination treatments with autophagy inhibitors. In mouse tumor xenografts, co-treatment with chloroquinone and BA145 led to a considerable reduction in tumor burden and angiogenesis compared to BA145 alone.
CONCLUSION: These studies reveal the essential role of BA145 triggered autophagy in the regulation of angiogenesis and cytoprotection. It also suggests that the combination of the autophagy inhibitors with chemotherapy or anti-angiogenic agents may be an effective therapeutic approach against cancer.
Mol Cancer. 2015 Jan;14():6.
PMID: 25608686 [PubMed - indexed for MEDLINE]
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| 122. |
An α-acetoxy-tirucallic acid isomer inhibits Akt/mTOR signaling and induces oxidative stress in prostate cancer cells.
El Gaafary M, Büchele B, Syrovets T, Agnolet S, Schneider B, Schmidt CQ, Simmet T
Here we provide evidence that αATA(8,24) (3α-acetyloxy-tir-8,24-dien-21-oic acid) inhibits Akt/mammalian target of rapamycin (mTOR) signaling. αATA(8,24) and other tirucallic acids were isolated from the acetylated extract of the oleo gum resin of Boswellia serrata to chemical homogeneity. Compared with related tirucallic acids, αATA(8,24) was the most potent inhibitor of the proliferation of androgen-insensitive prostate cancer cells in vitro and in vivo, in prostate cancer xenografted onto chick chorioallantoic membranes. αATA(8,24) induced loss of cell membrane asymmetry, caspase-3 activation, and DNA fragmentation in vitro and in vivo. These effects were selective for cancer cells, because αATA(8,24) exerted no overt toxic effects on peripheral blood mononuclear cells or the chick embryo. At the molecular level, αATA(8,24) inhibited the Akt1 kinase activity. Prior to all biochemical signs of cellular dysfunction, αATA(8,24) induced inhibition of the Akt downstream target mTOR as indicated by dephosphorylation of S6K1. This event was followed by decreased expression of cell cycle regulators, such as cyclin D1, cyclin E, and cyclin B1, as well as cyclin-dependent kinases CDK4 and CDK2 and phosphoretinoblastoma protein, which led to inhibition of the cell-cycle progression. In agreement with the mTOR inhibition, αATA(8,24) and rapamycin increased the volume of acidic vesicular organelles. In contrast to rapamycin, αATA(8,24) destabilized lysosomal and mitochondrial membranes and induced reactive oxygen species production in cancer cells. The ability of αATA(8,24) to inhibit Akt/mTOR signaling and to induce simultaneously oxidative stress could be exploited for the development of novel antitumor therapeutics with a lower profile of toxic side effects.
J Pharmacol Exp Ther. 2015 Jan;352(1):33-42.
PMID: 25316122 [PubMed - indexed for MEDLINE]
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| 123. |
Effect of boswellia thurifera gum methanol extract on cytotoxicity and p53 gene expression in human breast cancer cell line.
Yazdanpanahi N, Behbahani M, Yektaeian A
Boswellia has been widely used in traditional medicine for the treatment of different diseases such as cancer in Iran. The aim of this study was to evaluate the effect of the gum methanol extract of Boswellia thurifera on the viability and P53 gene expression of cultured breast cancer cells. The gum methanol extract was obtained in various concentrations using the maceration method. Normal (HEK-293) and cancer (MDA-MB-231) human cells were cultured and treated with various concentrations of the extract. Then MTT assay was used for the study of cytotoxic effect of the extract and real time PCR method was also applied for the investigation of P53 gene expression in cancer cells. The IC50 of the extract against cancer cells was 80 µg/mL and had less cytotoxic effect in normal cells. The effect of the extract was dose dependent. Induction of P53 expression by extract was also significantly more in treated cancer cells than untreated cells. This inductive effect in cells was higher after 12 h treatment than it was after 6 h. The results of the current study show that gum methanol extract of Boswellia thurifera has probably anti-cancer effects and could induce P53 gene transcription and toxicity in the cultured breast cancer cell line. The increase of P53 gene specific mRNA may be a mechanism of gum methanol extract induced cytotoxicity. However, for a definitive conclusion, further studies on other cell lines as well as animal models and subsequent clinical studies are warranted.
Iran J Pharm Res. 2014;13(2):719-24.
PMID: 25237368 [PubMed - as supplied by publisher]
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| 124. |
Caspase mediated synergistic effect of Boswellia serrata extract in combination with doxorubicin against human hepatocellular carcinoma.
Khan MA, Singh M, Khan MS, Najmi AK, Ahmad S
The study investigated the growth-inhibiting and apoptosis mediating effects of B. serrata extract as monotherapy and combination therapy with DOX against hepatocellular carcinoma cell lines. Boswellic acid rich fraction of B. serrata extract was prepared. MTT assay on HepG2 and Hep3B cells was carried out using B. serrata alone and in combination with DOX. Further, caspase-3 activity, TNF-α level, and IL-6 level were estimated. Isobolographic analysis was carried out to evaluate the effect of combination therapy. Additionally, protective effect of B. serrata extract on DOX induced hepatic toxicity was also evaluated in Wistar rats. B. serrata extract inhibited growth of HepG2 (IC50 value of 21.21 ± 0.92 μg/mL) as well as HepG2 (IC50 value of 18.65 ± 0.71 μg/mL). DOX inhibited growth in HepG2 and Hep3B cells with an IC50 of 1.06 ± 0.04 μg/mL and 1.92 ± 0.09 μg/mL. Isobolographic analysis showed combination index (CI) of DOX and B. serrata extract of 0.53 ± 0.03 to 0.79 ± 0.02 suggesting synergistic behavior against the two cell lines. B. serrata extract also caused dose dependent increase in caspase-3 activity, TNF-α level, and IL-6 level which was higher (P < 0.001) with DOX (1 μM) and B. serrata extract (20 μg/mL) combination. B. serrata extract also protected Wistar rats against DOX induced hepatic toxicity.
Biomed Res Int. 2014;2014():294143.
PMID: 25177685 [PubMed - indexed for MEDLINE]
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| 125. |
Design, synthesis and biological evaluation of β-boswellic acid based HDAC inhibitors as inducers of cancer cell death.
Sharma S, Ahmad M, Bhat JA, Kumar A, Kumar M, Zargar MA, Hamid A, Shah BA
The synthesis and bio-evaluation of naturally occurring boswellic acids (BAs) as an alternate CAP for the design of new HDAC inhibitors is described. All the compounds were screened against a panel of human cancer cell lines to identify leads, which were subsequently examined for their potential to inhibit HDACs. The identified lead compound showed IC50 value of 6μm for HDACs, found to induce G1 cell cycle arrest at significantly low concentration (1μM) and caused significant loss in mitochondrial membrane potential at 5 and 10μM. Furthermore, specific interactions of the lead molecule inside the catalytic domain were also studied through in silico molecular modeling.
Bioorg Med Chem Lett. 2014 Oct;24(19):4729-4734.
PMID: 25176189 [PubMed - indexed for MEDLINE]
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| 126. |
Differential effects of selective frankincense (Ru Xiang) essential oil versus non-selective sandalwood (Tan Xiang) essential oil on cultured bladder cancer cells: a microarray and bioinformatics study.
Dozmorov MG, Yang Q, Wu W, Wren J, Suhail MM, Woolley CL, Young DG, Fung KM, Lin HK
BACKGROUND: Frankincense (Boswellia carterii, known as Ru Xiang in Chinese) and sandalwood (Santalum album, known as Tan Xiang in Chinese) are cancer preventive and therapeutic agents in Chinese medicine. Their biologically active ingredients are usually extracted from frankincense by hydrodistillation and sandalwood by distillation. This study aims to investigate the anti-proliferative and pro-apoptotic activities of frankincense and sandalwood essential oils in cultured human bladder cancer cells.
METHODS: The effects of frankincense (1,400-600 dilutions) (v/v) and sandalwood (16,000-7,000 dilutions) (v/v) essential oils on cell viability were studied in established human bladder cancer J82 cells and immortalized normal human bladder urothelial UROtsa cells using a colorimetric XTT cell viability assay. Genes that responded to essential oil treatments in human bladder cancer J82 cells were identified using the Illumina Expression BeadChip platform and analyzed for enriched functions and pathways. The chemical compositions of the essential oils were determined by gas chromatography-mass spectrometry.
RESULTS: Human bladder cancer J82 cells were more sensitive to the pro-apoptotic effects of frankincense essential oil than the immortalized normal bladder UROtsa cells. In contrast, sandalwood essential oil exhibited a similar potency in suppressing the viability of both J82 and UROtsa cells. Although frankincense and sandalwood essential oils activated common pathways such as inflammatory interleukins (IL-6 signaling), each essential oil had a unique molecular action on the bladder cancer cells. Heat shock proteins and histone core proteins were activated by frankincense essential oil, whereas negative regulation of protein kinase activity and G protein-coupled receptors were activated by sandalwood essential oil treatment.
CONCLUSION: The effects of frankincense and sandalwood essential oils on J82 cells and UROtsa cells involved different mechanisms leading to cancer cell death. While frankincense essential oil elicited selective cancer cell death via NRF-2-mediated oxidative stress, sandalwood essential oil induced non-selective cell death via DNA damage and cell cycle arrest.
Chin Med. 2014;9():18.
PMID: 25006348 [PubMed - as supplied by publisher]
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| 127. |
Boswellia ovalifoliolata abrogates ROS mediated NF-κB activation, causes apoptosis and chemosensitization in Triple Negative Breast Cancer cells.
Thummuri D, Jeengar MK, Shrivastava S, Areti A, Yerra VG, Yamjala S, Komirishetty P, Naidu VG, Kumar A, Sistla R
The present study was aimed to evaluvate the apoptogenic potential of ethanolic extract of leaves from Boswellia ovalifoliolata (BL EthOH) and to unravel the molecular mechanisms implicated in apoptosis of Triple Negative Breast Cancer (TNBC) cells. BL EthOH was cytotoxic against TNBC cells like MDA-MB-231 and MDA-MB-453 with IC₅₀ concentrations 67.48 ± 5.45 and 70.03 ± 4.76 μg/ml, respectively. Apoptotic studies showed that BL EthOH was able to induce apoptosis and western blot studies demonstrated that BL EthOH significantly decreased the Phospho-NF-κB (ser536), PCNA, anti-apoptotic protein Bcl-2 expression and increased the expression of pro-apoptotic protein Bax, in MDA-MB-231 and MDA-MB-453 cell lines when compared with untreated cells. Besides, BL EthOH has synergistic chemosensitizing effects on TNBC cells and increased the cytotoxicity of doxorubicin and cisplatin.
Environ Toxicol Pharmacol. 2014 Jul;38(1):58-70.
PMID: 24908637 [PubMed - indexed for MEDLINE]
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| 128. |
Ultrastructural and hormonal changes in rat cauda epididymal spermatozoa induced by Boswellia papyrifera and Boswellia carterii.
Ahmed M, Ali D, Harrath AH, Hussain T, Al-Daghri N, Alokail MS, Aladakatti RH, Ghodesawar MA
Boswellia papyrifera and Boswellia carterii diffuses smoke polluting air that adversely affects indoor environment that certainly harm human health. Therefore, this study aims at ascertaining the effect of these plants on gonadal hormones and molecular changes in rat spermatozoa. The animals were exposed to 4 g/kg body weight of B. papyrifera and B. carterii daily for 120 days along with suitable controls. Significant decreases in FSH, LH and testosterone levels were evidenced, along with a reduction of protein, sialic acid, and carnitine levels. In sperm physiology, sperm count, motility, speed decrease, whereas sperm anomalies increase. TEM observation indicates morphological changes in plasma and acrosomal membranes, cytoplasmic droplet in the tail region, vacuolated, and disorganization of the mitochondrial sheath. These findings demonstrate that B. papyrifera and B. carterii smoke affects the process of sperm formation and maturation, which indicates the detrimental effects of these plants on the reproductive system.
C R Biol. 2014 Apr;337(4):250-7.
PMID: 24702894 [PubMed - indexed for MEDLINE]
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| 129. |
The comparative study of acetyl-11-keto-beta-boswellic acid (AKBA) and aspirin in the prevention of intestinal adenomatous polyposis in APC(Min/+) mice.
Wang R, Wang Y, Gao Z, Qu X
Acetyl-11-keto-beta-BA (AKBA), a component of the gum resin of Boswellia serrata, has been recognized as a promising agent for the prevention of intestinal tumorigenesis. Aspirin, a non-steroidal anti-inflammatory drug (NSAID), has also been considered to have the activity against intestinal tumorigenesis. However, the prevention of colonic cancer is insufficient and no definitive recommendation has been made for clinic use. Herein, we compared the efficacy of AKBA with that of aspirin in an adenomatous polyposis coli intestinal neoplasia consecutive weeks. Mice were sacrificed by anesthetizing. The whole intestine was removed from each mouse. The number, size and histopathology of intestinal adenomatous polyps were examined under microscopy. The adenomatous polyps were removed for further analysis by the assays of western blotting and immunohistochemical staining. AKBA significantly prevented the formation of intestinal adenomatous polyps without toxicity to mice. Statistical analysis indicated that AKBA's activity both in the prevention of small intestinal and colonic polyps was more potently than aspirin. Histopathologic examination revealed that AKBA's effect, that is the reduction of polyp size and degree of dysplasia, was more prominent in larger sized polyps, especially those originating in colon. These effects of AKBA were associated with its role in the induction of apoptosis in carcinomas. The assays of western blotting and immunohistochemistry staining indicated that the efficacy of AKBA might arise from its activity in the modulation of the Wnt/β-catenin pathway and NF-κB/COX-2 pathway in adenomatous polyps. Conclusion, AKBA by oral application prevented intestinal tumorigenesis more potential than aspirin.
Drug Discov Ther. 2014 Feb;8(1):25-32.
PMID: 24647155 [PubMed - indexed for MEDLINE]
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| 130. |
Major constituents of Boswellia carteri resin exhibit cyclooxygenase enzyme inhibition and antiproliferative activity.
Ali SI, Zhang CR, Mohamed AA, El-Baz FK, Hegazy AK, Kord MA, Nair MG
Aromatic gum from Boswellia carteri (olibanum oleogum) has long been used in Egyptian traditional medicine. Cyclooxygenase-1 (COX-1) enzyme inhibitory assay guided purification of the extracts of this resin resulted in five bioactive compounds, 3alpha-O-acetyl-8,24-dien-tirucallic acid (1), verticilla-4(20),7,11-triene (2), cembrene A (3), incensole acetate (4), and incensole (5). The pure isolates were investigated for their inhibitory effects on COX-1 and -2 enzymes and human tumor cell lines Hep-G2, MCF-7 and RAW 264.7. Compounds 1-5 inhibited COX-2 enzyme by 39.0, 32.7, 60.0, 46.3, and 49.8%, respectively. Furthermore, compound 2 showed an inhibitory concentration of 50% (IC50) at 9 microg/mL against Hep-G2 tumor cell line. This is the first report of COX-1 and -2 enzyme and tumor cell proliferation inhibitory effects of compounds 1 and 2.
Nat Prod Commun. 2013 Oct;8(10):1365-6.
PMID: 24354175 [PubMed - indexed for MEDLINE]
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| 131. |
Reversal of boswellic acid analog BA145 induced caspase dependent apoptosis by PI3K inhibitor LY294002 and MEK inhibitor PD98059.
Pathania AS, Joshi A, Kumar S, Guru SK, Bhushan S, Sharma PR, Bhat WW, Saxena AK, Singh J, Shah BA, Andotra SS, Taneja SC, Malik FA, Kumar A
PI3K/Akt and ERK pathways are important for growth and proliferation of many types of cancers. Therefore, PI3K inhibitor LY294002 (LY) and MEK1/2 inhibitor PD98059 (PD) are used to sensitize many types of cancer cell lines to chemotherapeutic agents, where AKT and ERK pathways are over activated. However, in this study, we show for the first time that PD could protect the leukemia cells independent of ERK pathway inhibition, besides, we also report a detailed mechanism for antiapoptotic effect of LY in HL-60 cells against the cytotoxicity induced by a boswellic acid analog BA145. Apoptosis induced by BA145 is accompanied by downregulation of PI3K/Akt and ERK pathways in human myelogenous leukemia HL-60 cells, having activating N-Ras mutation. Both LY and PD protected the cells against mitochondrial stress caused by BA145, and reduced the release of cytochrome c and consequent activation of caspase-9. LY and PD also diminished the activation of caspase-8 without affecting the death receptors. Besides, LY and PD also reversed the caspase dependent DNA damage induced by BA145. Further studies revealed that LY and PD significantly reversed the inhibitory effect of BA145 on cell cycle regulatory proteins by upregulating hyperphosphorylated retinoblastoma, pRB (S795) and downregulating p21 and cyclin E. More importantly, all these events were reversed by caspase inhibition by Z-VAD-fmk, suggesting that both LY and PD act at the level of caspases to diminish the apoptosis induced by BA145. These results indicate that inhibitors of PI3K/Akt and ERK pathways can play dual role and act against chemotherapeutic agents.
Apoptosis. 2013 Dec;18(12):1561-73.
PMID: 23948751 [PubMed - indexed for MEDLINE]
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| 132. |
Acetyl-11-keto-beta-boswellic acid (AKBA) prevents human colonic adenocarcinoma growth through modulation of multiple signaling pathways.
Yuan Y, Cui SX, Wang Y, Ke HN, Wang RQ, Lou HX, Gao ZH, Qu XJ
BACKGROUND: Acetyl-11-keto-beta-boswellic acid (AKBA) is a derivative of boswellic acid. We have previously reported that AKBA can reduce the number and size of colonic adenomatous polyps in the APC(Min/+) mouse model. In this study, we evaluated the effect of AKBA on human colonic adenocarcinoma growth. Its efficacy and toxicity were compared with those of the non-steroidal anti-inflammatory drug aspirin.
METHODS: The inhibition of cancer cell growth was estimated by colorimetric and clonogenic assay. Cell cycle distribution was analyzed by the flow cytometry assay. Annexin V-FITC/PI staining and JC-1 fluorescence probe assays were performed to determine the apoptotic cells. Further experiment was carried out in mice with HT-29 xenografts. AKBA was orally administered for 24days. The HT-29 xenografts were removed for TUNEL staining and western blotting analysis. Blood was obtained for clinical chemical analysis, and samples of organs were sectioned for microscopic assessment.
RESULTS: AKBA significantly inhibited human colon adenocarcinoma growth, showing arrest of the cell cycle in G1-phase and induction of apoptosis. AKBA administration in mice effectively delayed the growth of HT-29 xenografts without signs of toxicity. The activity of AKBA was more potent than that of aspirin. Western blotting suggested that this activity may arise from its multiple effects on the activation of apoptotic proteins, suppression of inflammatory cytokines and modulation of EGFR and ATM/P53 signaling pathways in the HT-29 xenografts.
CONCLUSIONS: AKBA prevents the growth of colonic adenocarcinoma through modulation of multiple signaling pathways.
GENERAL SIGNIFICANCE: AKBA could be a promising agent in the prevention of colonic adenocarcinomas.
Biochim Biophys Acta. 2013 Oct;1830(10):4907-16.
PMID: 23850473 [PubMed - indexed for MEDLINE]
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| 133. |
Dietary phytochemicals as potent chemotherapeutic agents against breast cancer: Inhibition of NF-κB pathway via molecular interactions in rel homology domain of its precursor protein p105.
Khan MK, Ansari IA, Khan MS
BACKGROUND: Dietary phytochemicals consist of a wide variety of biologically active compounds that are ubiquitous in plants, many of which have been reported to have anti-tumor as well as anti-inflammatory properties.
OBJECTIVE: In the present study, we aimed to validate these findings by using docking protocols and explicate the possible mechanism of action for a dataset of nine phytochemicals namely boswellic acid, 1-caffeoylquinic acid, ellagic acid, emodin, genistein, guggulsterone, quercetin, resveratrol, and sylibinin from different plants against the nuclear factor- kappaB (NF-κB) precursor protein p105, an important transcription factor reported to be overexpressed in breast cancer.
MATERIALS AND METHODS: 2-D structures of all phytochemicals were retrieved from PubChem Compound database and their subsequent conversion into 3-D structures was performed by using online software system CORINA. The X-ray crystallographic structure of the NF-κB precursor p105 was extracted from Brookhaven Protein Data Bank. Molecular docking simulation study was carried out by using AutoDock Tools 4.0.
RESULTS: Our results showed significant binding affinity of different phytochemicals with the Rel homology domain of the NF-κB precursor protein p105. Quercetin and 1-caffeoylquinic acid were found to be very effective inhibitors against target molecule as they showed binding energy of -12.11 and -11.50 Kcal/mol, respectively. The order of affinity of other ligands with p105 was found as follows: guggulsterone > sylibinin > emodin > resveratrol > genistein > boswellic acid > ellagic acid.
CONCLUSION: Our in silico study has explored the possible chemopreventive mechanism of these phytochemicals against the NF-κB precursor protein p105 and deciphered that quercetin, 1-caffeoylquinic acid and guggulsterone were the potent inhibitors against target molecule. In addition, large scale preclinical and clinical trials are needed to explore the role of these chemotherapeutic molecules against the NF-κB precursor protein p105 in cure and prevention of breast cancer.
Pharmacogn Mag. 2013 Jan;9(33):51-7.
PMID: 23661994 [PubMed - as supplied by publisher]
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| 134. |
Boswellic acid and its inhibitory effect on tumor growth in systemic malignancies: an emerging concept in oncology.
Kapoor S
Future Oncol. 2013 May;9(5):627-8.
PMID: 23647290 [PubMed - indexed for MEDLINE]
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| 135. |
Acetyl-11-keto-β-boswellic acid (AKBA) inhibits human gastric carcinoma growth through modulation of the Wnt/β-catenin signaling pathway.
Zhang YS, Xie JZ, Zhong JL, Li YY, Wang RQ, Qin YZ, Lou HX, Gao ZH, Qu XJ
BACKGROUND: Acetyl-11-keto-beta-boswellic acid (AKBA) is a derivative of boswellic acid, an active component of Boswellia serrata gum resin. We examined the effect of AKBA on human gastric carcinoma growth and explored the underlying molecular mechanisms.
METHODS: Inhibition of cancer cell growth was estimated by colorimetric and clonogenic assays. Cell cycle distribution was analyzed by flow cytometry and apoptosis determined using Annexin V-FITC/PI staining and DNA ladder quantification. After three weeks of oral AKBA administration in nude mice bearing cancer xenografts, animals were sacrificed and xenografts removed for TUNEL staining and western blot analysis.
RESULTS: AKBA exhibited anti-cancer activity in vitro and in vivo. With oral application in mice, AKBA significantly inhibited SGC-7901 and MKN-45 xenografts without toxicity. This effect might be associated with its roles in cell cycle arrest and apoptosis induction. The results also showed activation of p21(Waf1/Cip1) and p53 in mitochondria and increased cleaved caspase-9, caspase-3, and PARP and Bax/Bcl-2 ratio after AKBA treatment. Further analysis suggested that these effects might arise from AKBA's modulation of the aberrant Wnt/β-catenin signaling pathway. Upon AKBA treatment, β-catenin expression in nuclei was inhibited, and membrane β-catenin was activated. In the same sample, active GSK3β was increased and its non-active form decreased. Levels of cyclin D1, PCNA, survivin, c-Myc, MMP-2, and MMP-7, downstream targets of Wnt/β-catenin, were inhibited.
CONCLUSIONS: AKBA effects on human gastric carcinoma growth were associated with its activity in modulating the Wnt/β-catenin signaling pathway.
GENERAL SIGNIFICANCE: AKBA could be useful in the treatment of gastric cancers.
Biochim Biophys Acta. 2013 Jun;1830(6):3604-15.
PMID: 23500016 [PubMed - indexed for MEDLINE]
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| 136. |
Frankincense essential oil prepared from hydrodistillation of Boswellia sacra gum resins induces human pancreatic cancer cell death in cultures and in a xenograft murine model.
Ni X, Suhail MM, Yang Q, Cao A, Fung KM, Postier RG, Woolley C, Young G, Zhang J, Lin HK
BACKGROUND: Regardless of the availability of therapeutic options, the overall 5-year survival for patients diagnosed with pancreatic cancer remains less than 5%. Gum resins from Boswellia species, also known as frankincense, have been used as a major ingredient in Ayurvedic and Chinese medicine to treat a variety of health-related conditions. Both frankincense chemical extracts and essential oil prepared from Boswellia species gum resins exhibit anti-neoplastic activity, and have been investigated as potential anti-cancer agents. The goals of this study are to identify optimal condition for preparing frankincense essential oil that possesses potent anti-tumor activity, and to evaluate the activity in both cultured human pancreatic cancer cells and a xenograft mouse cancer model.
METHODS: Boswellia sacra gum resins were hydrodistilled at 78°C; and essential oil distillate fractions were collected at different durations (Fraction I at 0-2 h, Fraction II at 8-10 h, and Fraction III at 11-12 h). Hydrodistillation of the second half of gum resins was performed at 100°C; and distillate was collected at 11-12 h (Fraction IV). Chemical compositions were identified by gas chromatography-mass spectrometry (GC-MS); and total boswellic acids contents were quantified by high-performance liquid chromatography (HPLC). Frankincense essential oil-modulated pancreatic tumor cell viability and cytotoxicity were determined by colorimetric assays. Levels of apoptotic markers, signaling molecules, and cell cycle regulators expression were characterized by Western blot analysis. A heterotopic (subcutaneous) human pancreatic cancer xenograft nude mouse model was used to evaluate anti-tumor capability of Fraction IV frankincense essential oil in vivo. Frankincense essential oil-induced tumor cytostatic and cytotoxic activities in animals were assessed by immunohistochemistry.
RESULTS: Longer duration and higher temperature hydrodistillation produced more abundant high molecular weight compounds, including boswellic acids, in frankincense essential oil fraactions. Human pancreatic cancer cells were sensitive to Fractions III and IV (containing higher molecular weight compounds) treatment with suppressed cell viability and increased cell death. Essential oil activated the caspase-dependent apoptotic pathway, induced a rapid and transient activation of Akt and Erk1/2, and suppressed levels of cyclin D1 cdk4 expression in cultured pancreatic cancer cells. In addition, Boswellia sacra essential oil Fraction IV exhibited anti-proliferative and pro-apoptotic activities against pancreatic tumors in the heterotopic xenograft mouse model.
CONCLUSION: All fractions of frankincense essential oil from Boswellia sacra are capable of suppressing viability and inducing apoptosis of a panel of human pancreatic cancer cell lines. Potency of essential oil-suppressed tumor cell viability may be associated with the greater abundance of high molecular weight compounds in Fractions III and IV. Although chemical component(s) responsible for tumor cell cytotoxicity remains undefined, crude essential oil prepared from hydrodistillation of Boswellia sacra gum resins might be a useful alternative therapeutic agent for treating patients with pancreatic adenocarcinoma, an aggressive cancer with poor prognosis.
BMC Complement Altern Med. 2012 Dec;12():253.
PMID: 23237355 [PubMed - indexed for MEDLINE]
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| 137. |
Enhanced anticancer potential of encapsulated solid lipid nanoparticles of TPD: a novel triterpenediol from Boswellia serrata.
Bhushan S, Kakkar V, Pal HC, Guru SK, Kumar A, Mondhe DM, Sharma PR, Taneja SC, Kaur IP, Singh J, Saxena AK
A pentacyclic triterpenediol (TPD) from Boswellia serrata has significant cytotoxic and apoptotic potential in a large number of human cancer cell lines. To enhance its anticancer potential, it was successfully formulated into solid lipid nanoparticles (SLNs) by the microemulsion method with 75% drug entrapment efficiency. SEM and TEM studies indicated that TPD-SLNs were regular, solid, and spherical particles in the range of 100-200 nm, and the system indicated that they were more or less stable upon storing up to six months. TPD loaded SLNs showed significantly higher cytotoxic/antitumor potential than the parent drug. TPD-SLNs have 40-60% higher cytotoxic and apoptotic potential than the parent drug in terms of IC(50), extent of apoptosis, DNA damage, and expression of pro-apoptotic proteins like TNF-R1, cytochrome-c, and PARP cleavage in HL-60 cells. Moreover, blank SLNs did not have any cytotoxic effect on the cancer as well as in normal mouse peritoneal macrophages. The in vivo antitumor potential of TPD-SLNs was significantly higher than that of TPD alone in Sarcoma-180 solid tumor bearing mice. Therefore, SLNs of TPD successfully increased the apoptotic and anticancer potential of TPD at comparable doses (both in vitro and in vivo). This work provides new insight into improvising the therapeutic efficacy of TPD by adopting novel delivery strategies such as solid lipid nanoparticles.
Mol Pharm. 2013 Jan;10(1):225-35.
PMID: 23237302 [PubMed - indexed for MEDLINE]
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| 138. |
A novel semisynthetic inhibitor of the FRB domain of mammalian target of rapamycin blocks proliferation and triggers apoptosis in chemoresistant prostate cancer cells.
Morad SA, Schmid M, Büchele B, Siehl HU, El Gafaary M, Lunov O, Syrovets T, Simmet T
The mammalian target of rapamycin (mTOR) is a key regulator of cell growth and its uncontrolled activation is a hallmark of cancer. Moreover, mTOR activation has been implicated in the resistance of cancer cells to many anticancer drugs, rendering this pathway a promising pharmacotherapeutic target. Here we explored the capability of a semisynthetic compound to intercept mTOR signaling. We synthesized and chemically characterized a novel, semisynthetic triterpenoid derivative, 3-cinnamoyl-11-keto-β-boswellic acid (C-KβBA). Its pharmacodynamic effects on mTOR and several other signaling pathways were assessed in a number of prostate and breast cancer cell lines as well as in normal prostate epithelial cells. C-KβBA exhibits specific antiproliferative and proapoptotic effects in cancer cell lines in vitro as well as in PC-3 prostate cancer xenografts in vivo. Mechanistically, the compound significantly inhibits the cap-dependent transition machinery, decreases expression of eukaryotic translation initiation factor 4E and cyclin D1, and induces G(1) cell-cycle arrest. In contrast to conventional mTOR inhibitors, C-KβBA downregulates the phosphorylation of p70 ribosomal S6 kinase, the major downstream target of mTOR complex 1, without concomitant activation of mTOR complex 2/Akt and extracellular signal-regulated kinase pathways, and independently of protein phosphatase 2A, liver kinase B1/AMP-activated protein kinase/tuberous sclerosis complex, and F12-protein binding. At the molecular level, the compound binds to the FKBP12-rapamycin-binding domain of mTOR with high affinity, thereby competing with the endogenous mTOR activator phosphatidic acid. C-KβBA represents a new type of proapoptotic mTOR inhibitor that, due to its special mechanistic profile, might overcome the therapeutic drawbacks of conventional mTOR inhibitors.
Mol Pharmacol. 2013 Feb;83(2):531-41.
PMID: 23208958 [PubMed - indexed for MEDLINE]
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| 139. |
NF-κB down-regulation and PARP cleavage by novel 3-α-butyryloxy-β-boswellic acid results in cancer cell specific apoptosis and in vivo tumor regression.
Qurishi Y, Hamid A, Sharma PR, Wani ZA, Mondhe DM, Singh SK, Zargar MA, Andotra SS, Shah BA, Taneja SC, Saxena AK
The present study relates to the induction of apoptosis thereof cytotoxicity and anti-cancer activity displayed by semi-synthetic analog of Boswellic acid i.e. 3-α-Butyryloxy-β-boswellic acid (BOBA). The cytotoxicity data revealed the differential sensitivity of cancer cell lines towards BOBA which may display its impact against different types of cancers. Considering the inhibitory potential of BOBA, we further sought to understand the target for BOBA deciphering the mechanism of action leading to apoptotic cell death and it was for the first time reported about the triterpenoid ring especially the β-boswellic acid derivative is targeting PI3K pathway. Our data revealed that BOBA treatment provides evidence about the apoptotic nature showing the potential of targeting mitochondria dependent pathways during apoptosis in HL-60 cells. BOBA induced hypo-diploid sub-G(1) DNA population in HL-60 cells as was also evident from the pattern of DNA fragmentation and mitochondrial membrane potential (ΛΨm) loss. Morphological analysis under fluorescent and scanning electron microscopy displayed typical features such as cell shrinkage, membrane blebbing, chromatin condensation and nuclear fragmentation. These events paralleled with the down-regulation of NF-κB and induced PARP cleavage. Furthermore, it is noteworthy that BOBA also depicted significant growth inhibition in Ehrlich Ascitic Tumour (EAT), Ehrlich Ascitic Carcinoma (EAC) and Sarcoma- 180 tumour models. Taken together, BOBA treatment may represent as potential agent to the currently available anticancer agents in both prophylactic and/or therapeutic applications. Also, our findings may open up a new perspective in the construction of novel anticancer agents based on boswellic acids that will facilitate the development of these agents for anticancer therapeutics.
Anticancer Agents Med Chem. 2013 Jun;13(5):777-90.
PMID: 23157593 [PubMed - indexed for MEDLINE]
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| 140. |
Chemoprevention of intestinal adenomatous polyposis by acetyl-11-keto-beta-boswellic acid in APC(Min/+) mice.
Liu HP, Gao ZH, Cui SX, Wang Y, Li BY, Lou HX, Qu XJ
Acetyl-11-keto-beta-boswellic acid (AKBA) is a derivative of boswellic acid, which is an active component of the gum resin of Boswellia serrata. AKBA has been used as an adjuvant medication for treatment of inflammatory diseases. In this study, we aimed to evaluate the efficacy of AKBA as a chemopreventive agent against intestinal adenomatous polyposis in the adenomatous polyposis coli multiple intestinal neoplasia (APC(Min/+) ) mouse model. APC(Min/+) mice were administered AKBA by p.o. gavage for 8 consecutive weeks. The mice were sacrificed and the number, size and histopathology of intestinal polyps were examined by light microscopy. AKBA decreased polyp numbers by 48.9% in the small intestine and 60.4% in the colon. An even greater AKBA effect was observed in preventing the malignant progression of these polyps. The number of large (>3 cm) colonic polyposis was reduced by 77.8%. Histopathologic analysis demonstrated a significant reduction in the number of dysplastic cells and in the degree of dysplasia in each polyp after AKBA treatment. There was no evidence of high grade dysplasia or intramucosal carcinoma in any of the polyps examined within the treated group. More interestingly, interdigitated normal appearing intestinal villi were observed in the polyps of the treated group. During the course of the study, AKBA was well tolerated by the mice with no obvious signs of toxicity. Results from immunohistochemical staining, Western blotting and enzyme-linked immunosorbent assay indicated that the chemopreventive effect of AKBA was attributed to a collection of activities including antiproliferation, apoptosis induction, antiangiogenesis and anti-inflammation. AKBA was found to exert its chemopreventive action through the inhibition of the Wnt/β-catenin and NF-κB/cyclooxygenase-2 signaling pathways. Our findings suggest that AKBA could be a promising regimen in chemoprevention against intestinal tumorigenesis.
Int J Cancer. 2013 Jun;132(11):2667-81.
PMID: 23132636 [PubMed - indexed for MEDLINE]
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| 141. |
Boswellic acid exerts antitumor effects in colorectal cancer cells by modulating expression of the let-7 and miR-200 microRNA family.
Takahashi M, Sung B, Shen Y, Hur K, Link A, Boland CR, Aggarwal BB, Goel A
Colorectal cancer (CRC) is a complex disease with genetic and epigenetic alterations in many key oncogenes and tumor suppressor genes. The active principle of a gum resin from Boswellia serrata, 3-acetyl-11-keto-β-boswellic acid (AKBA), has recently gained attention as a chemopreventive compound due to its ability to target key oncogenic proteins such as 5-lipoxygenase and nuclear factor-kappaB. AKBA has been shown to inhibit the growth of CRC cells; however, the precise molecular mechanisms underlying its anticancer activities in CRC remain unclear. We hypothesized that boswellic acids may achieve their chemopreventive effects by modulating specific microRNA (miRNA) pathways. We found that AKBA significantly up-regulated expression of the let-7 and miR-200 families in various CRC cell lines. Both let-7 and miR-200 are putative tumor-suppressive miRNAs. AKBA modulated the expression of several downstream targets of the let-7 and miR-200 families, such as CDK6, vimentin and E-cadherin. These data were further strengthened by miRNA knockdown studies, which revealed that inhibition of let-7i facilitated enhanced cancer cell proliferation, migration and invasion. In addition, AKBA also induced similar modulation of the let-7 and miR-200 downstream genes in CRC tumors orthotopically implanted in nude mice. These results indicate that AKBA-induced antitumor effects in CRC occur, at least partly through the up-regulation of specific miRNA pathways. Our data provide novel evidence that anticancer effects of boswellic acids are due in part to their ability to regulate cellular epigenetic machinery and further highlight the promise for this phytochemical in the preventative and therapeutic applications of CRC.
Carcinogenesis. 2012 Dec;33(12):2441-9.
PMID: 22983985 [PubMed - indexed for MEDLINE]
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| 142. |
PARP cleavage and perturbance in mitochondrial membrane potential by 3-α-propionyloxy-β-boswellic acid results in cancer cell death and tumor regression in murine models.
Qurishi Y, Hamid A, Sharma PR, Wani ZA, Mondhe DM, Singh SK, Zargar MA, Andotra SS, Shah BA, Taneja SC, Saxena AK
BACKGROUND: Apoptotic induction in cancer cells has become a major focus of anticancer therapeutics. In this regard, β-boswellic acids, naturally occurring pentacyclic triterpenes, have demonstrated antiproliferative and cytotoxic effects against different types of cancers. Surprisingly, not much has been reported regarding the chemical modifications or preparation of structural analogs of the key constituents of β-boswellic acid.
AIM: The anticancer activity of 3-α-propionyloxy-β-boswellic acid (POBA) was investigated and this article reports for the first time that the triterpenoid ring of the boswellic acid derivative POBA is targeting the PI3K pathway.
MATERIALS & METHODS: Induction of apoptosis of the semi-synthetic derivative of β-boswellic acid-POBA in vitro was analyzed using a battery of human cancer cell lines followed by cell cycle phase distribution, further validated by DNA fragmentation, and was found to cause mitochondrial membrane potential loss with ultrastructural changes, as observed by electron microscopy studies and expression study using PARP cleavage, as well as validated by in vivo anti-tumor activity.
RESULTS: The cytotoxicity data revealed the sensitivity of various human cancer cell lines of varied tissue origin to β-boswellic acid, which robustly induced cell cycle arrest, DNA fragmentation and loss of mitochondrial membrane potential. Morphological studies of the effects of POBA revealed loss of surface projections, chromatin condensation, apoptotic body formation and POBA-mediated PARP cleavage. For in vivo therapeutic experiments, murine tumor models were treated with POBA and the treatment resulted in a significantly higher level of growth inhibition and apoptosis was significantly induced.
CONCLUSION: These findings demonstrate that acyl substituents/groups in the main skeleton of β-boswellic acid have the potential to be potent chemotherapeutic agents.
Future Oncol. 2012 Jul;8(7):867-81.
PMID: 22830406 [PubMed - indexed for MEDLINE]
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| 143. |
Boswellic acid induces epigenetic alterations by modulating DNA methylation in colorectal cancer cells.
Shen Y, Takahashi M, Byun HM, Link A, Sharma N, Balaguer F, Leung HC, Boland CR, Goel A
Accumulating evidence suggests that chemopreventive effects of some dietary polyphenols may in part be mediated by their ability to influence epigenetic mechanisms in cancer cells. Boswellic acids, derived from the plant Boswellia serrata, have long been used for the treatment of various inflammatory diseases due to their potent anti-inflammatory activities. Recent preclinical studies have also suggested that this compound has anti-cancer potential against various malignancies. However, the precise molecular mechanisms underlying their anti-cancer effects remain elusive. Herein, we report that boswellic acids modulate DNA methylation status of several tumor suppressor genes in colorectal cancer (CRC) cells. We treated RKO, SW48 and SW480 CRC cell lines with the active principle present in boswellic acids, acetyl-keto-β-boswellic acid (AKBA). Using genome-wide DNA methylation and gene expression microarray analyses, we discovered that AKBA induced a modest genome-wide demethylation that permitted simultaneous re-activation of the corresponding tumor suppressor genes. The quantitative methylation-specific PCR and RT-PCR validated the gene demethylation and re-expression in several putative tumor suppressor genes including SAMD14 and SMPD3. Furthermore, AKBA inhibited DNMT activity in CRC cells. Taken together, these results lend further support to the growing notion that anti-cancer effect of boswellic acids may in part be due to its ability to demethylate and reactivate methylation-silenced tumor suppressor genes. These results suggest that not only boswellic acid might be a promising epigenetic modulator in the chemoprevention and treatment of CRC, but also provide a rationale for future investigations on the usefulness of such botanicals for epigenetic therapy in other human malignancies.
Cancer Biol Ther. 2012 May;13(7):542-52.
PMID: 22415137 [PubMed - indexed for MEDLINE]
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| 144. |
[Chemopreventive effect of boswellic acid and curcumin on 7,12-dimethyl benzanthracene-induced hamster cheek pouch carcinogenesis].
Zhang XY, Chen XF, Sun Z, Miao CC, Ge LH, Tian ZC
OBJECTIVE: To evaluate the chemopreventive effects of boswellic acid and curcumin on 7,12-dimethyl benzanthracene(DMBA)-induced oral carcinogenesis in the hamster cheek pouch model.
METHODS: Male Syrian golden hamsters (6 - 8 weeks old, 80 - 130 g in weight) were randomly divided into seven groups, with group A serving as the untreated negative control. The left cheek pouch of the remaining hamsters was topically treated with 0.5% DMBA in mineral oil three times a week for 6 weeks. They were then randomized to six groups with group B serving as a positive control and receiving no further treatment. Groups C-G were treated topically with 5, 10 mg/L boswellic acid, 5, 10 µmol/L curcumin, or the combination of 5 mg/L boswellic acid and 5 µmol/L curcumin three times per week for 18 weeks. The animals were injected with bromodeoxyuridine intraperitoneally at 50 mg/kg 2 h prior to killing. At the 25 th week all the hamsters were sacrificed and cheek pouch tissue was harvested. One half of the tissue was snap frozen in liquid nitrogen for analysis of arachidonic acid metabolites, and the other half was fixed in 10% phosphate-buffered saline(PBS)-buffered formalin for histopathological examination.
RESULTS: Six-weeks of DMBA followed by 18-weeks of topical application of boswellic acid and curcumin, both boswellic acid (5, 10 mg/L) and curcumin (5, 10 µmol/L) significantly inhibited the incidence from 93.8% to 73.9% (P > 0.05), numbers from 2.19 ± 0.98 to 1.13 ± 0.81 (P < 0.01) and size of visible tumors. Microscopically the incidence of squamous cell carcinoma and BrdU index were also significantly suppressed by boswellic acid and curcumin.
CONCLUSIONS: Both boswellic acid and curcumin were effective in preventing oral carcinogenesis in DMBA-induced hamster cheek pouch model.
Zhonghua Kou Qiang Yi Xue Za Zhi. 2011 Nov;46(11):678-83.
PMID: 22333308 [PubMed - indexed for MEDLINE]
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| 145. |
Boswellia sacra essential oil induces tumor cell-specific apoptosis and suppresses tumor aggressiveness in cultured human breast cancer cells.
Suhail MM, Wu W, Cao A, Mondalek FG, Fung KM, Shih PT, Fang YT, Woolley C, Young G, Lin HK
BACKGROUND: Gum resins obtained from trees of the Burseraceae family (Boswellia sp.) are important ingredients in incense and perfumes. Extracts prepared from Boswellia sp. gum resins have been shown to possess anti-inflammatory and anti-neoplastic effects. Essential oil prepared by distillation of the gum resin traditionally used for aromatic therapy has also been shown to have tumor cell-specific anti-proliferative and pro-apoptotic activities. The objective of this study was to optimize conditions for preparing Boswellea sacra essential oil with the highest biological activity in inducing tumor cell-specific cytotoxicity and suppressing aggressive tumor phenotypes in human breast cancer cells.
METHODS: Boswellia sacra essential oil was prepared from Omani Hougari grade resins through hydrodistillation at 78 or 100 °C for 12 hours. Chemical compositions were identified by gas chromatography-mass spectrometry; and total boswellic acids contents were quantified by high-performance liquid chromatography. Boswellia sacra essential oil-mediated cell viability and death were studied in established human breast cancer cell lines (T47D, MCF7, MDA-MB-231) and an immortalized normal human breast cell line (MCF10-2A). Apoptosis was assayed by genomic DNA fragmentation. Anti-invasive and anti-multicellular tumor properties were evaluated by cellular network and spheroid formation models, respectively. Western blot analysis was performed to study Boswellia sacra essential oil-regulated proteins involved in apoptosis, signaling pathways, and cell cycle regulation.
RESULTS: More abundant high molecular weight compounds, including boswellic acids, were present in Boswellia sacra essential oil prepared at 100 °C hydrodistillation. All three human breast cancer cell lines were sensitive to essential oil treatment with reduced cell viability and elevated cell death, whereas the immortalized normal human breast cell line was more resistant to essential oil treatment. Boswellia sacra essential oil hydrodistilled at 100 °C was more potent than the essential oil prepared at 78 °C in inducing cancer cell death, preventing the cellular network formation (MDA-MB-231) cells on Matrigel, causing the breakdown of multicellular tumor spheroids (T47D cells), and regulating molecules involved in apoptosis, signal transduction, and cell cycle progression.
CONCLUSIONS: Similar to our previous observations in human bladder cancer cells, Boswellia sacra essential oil induces breast cancer cell-specific cytotoxicity. Suppression of cellular network formation and disruption of spheroid development of breast cancer cells by Boswellia sacra essential oil suggest that the essential oil may be effective for advanced breast cancer. Consistently, the essential oil represses signaling pathways and cell cycle regulators that have been proposed as therapeutic targets for breast cancer. Future pre-clinical and clinical studies are urgently needed to evaluate the safety and efficacy of Boswellia sacra essential oil as a therapeutic agent for treating breast cancer.
BMC Complement Altern Med. 2011 Dec;11():129.
PMID: 22171782 [PubMed - indexed for MEDLINE]
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| 146. |
Boswellic acid suppresses growth and metastasis of human pancreatic tumors in an orthotopic nude mouse model through modulation of multiple targets.
Park B, Prasad S, Yadav V, Sung B, Aggarwal BB
Pancreatic cancer (PaCa) is one of the most lethal cancers, with an estimated 5-year survival of <5% even when patients are given the best treatment available. In addition, these treatments are often toxic and expensive, thus new agents which are safe, affordable and effective are urgently needed. We describe here the results of our study with acetyl-11-keto-β-boswellic acid (AKBA), an agent obtained from an Ayurvedic medicine, gum resin of Boswellia serrata. Whether AKBA has an activity against human PaCa, was examined in in vitro models and in an orthotopic nude mouse model of PaCa. We found that AKBA inhibited the proliferation of four different PaCa cell lines (AsPC-1, PANC-28, and MIA PaCa-2 with K-Ras and p53 mutations, and BxPC-3 with wild-type K-Ras and p53 mutation). These effects correlated with an inhibition of constitutively active NF-κB and suppression of NF-κB regulating gene expression. AKBA also induced apoptosis, and sensitized the cells to apoptotic effects of gemcitabine. In the orthotopic nude mouse model of PaCa, p.o. administration of AKBA alone (100 mg/kg) significantly inhibited the tumor growth; this activity was enhanced by gemcitabine. In addition, AKBA inhibited the metastasis of the PaCa to spleen, liver, and lungs. This correlated with decreases in Ki-67, a biomarker of proliferation, and CD31, a biomarker of microvessel density, in the tumor tissue. AKBA produced significant decreases in the expression of NF-κB regulating genes in the tissues. Immunohistochemical analysis also showed AKBA downregulated the expression of COX-2, MMP-9, CXCR4, and VEGF in the tissues. Overall these results demonstrate that AKBA can suppress the growth and metastasis of human pancreatic tumors in an orthotopic nude mouse model that correlates with modulation of multiple targets.
PLoS One. 2011;6(10):e26943.
PMID: 22066019 [PubMed - indexed for MEDLINE]
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| 147. |
Targeting Sp1 transcription factors in prostate cancer therapy.
Sankpal UT, Goodison S, Abdelrahim M, Basha R
Transcription factors are proteins that regulate gene expression by binding to specific DNA sequences within gene promoter regions. Specificity protein (Sp) family transcription factors play a critical role in various cellular processes and have been shown to be associated with tumorigenesis. The Sp family consists of several members that contain a highly conserved DNA-binding domain composed of three zinc fingers at the C-terminus and serine/threonine- and glutamine-rich transactivation domains at the N-terminal. Sp1 is elevated in several cancers including prostate and is associated with the prognosis of patients. Sp1, Sp3, and Sp4 regulate a variety of cancer associated genes that are involved in cell cycle, proliferation, cell differentiation, and apoptosis. Studies have shown that in prostate cancer, Sp1 regulates important genes like androgen receptor, TGF-β, c-Met, fatty acid synthase, matrix metalloprotein (MT1-MMP), PSA, and α-integrin. These results highlight the importance of Sp1 in prostate cancer and emphasize the potential therapeutic value of targeting Sp1. Several strategies, including the use of natural and synthetic compounds, have been used to inhibit Sp1 in prostate cancer. These include polyphenol quercetin, betulinic acid, acetyl-11-keto-beta-boswellic acid, tea phenols, isothiocyanates, thiazolidinediones, arsenic trioxide, and selenium. This review will describe the association of Sp proteins in prostate cancer with a special emphasis on some of the agents tested to target Sp proteins for the treatment of this malignancy.
Med Chem. 2011 Sep;7(5):518-25.
PMID: 22022994 [PubMed - indexed for MEDLINE]
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| 148. |
Potentiation of the antitumor effect of 11-keto-β-boswellic acid by its 3-α-hexanoyloxy derivative.
Chashoo G, Singh SK, Mondhe DM, Sharma PR, Andotra SS, Shah BA, Taneja SC, Saxena AK
We recently discovered that a propionyloxy derivative of 11-keto-β-boswellic acid (PKBA) showed better anticancer potential than other boswellic acids including AKBA, encompassing the importance of acyl group at the 3-α-hydroxy position of KBA. In continuation of our previous work, other higher derivatives (with increasing alkoxy chain length at 3-α-hydroxy position) including butyryloxy (BKBA) and hexanoyloxy (HKBA) derivatives of KBA were synthesized. The respective IC(50) values of BKBA and HKBA in HL-60 cells were found to be 7.7 and 4.5 μg/ml. IC(50) value of HKBA was comparatively lower than that of BKBA, and further lower than that of the previously reported derivative (PKBA, IC(50) 8.7 μg/ml). In order to compare the anticancer potential of HKBA with PKBA, detailed in vitro pro-apoptotic and in vivo anticancer studies were carried out. The induction of apoptosis by HKBA was measured using various parameters including fluorescence and scanning electron microscopy, DNA fragmentation and Annexin V-FITC binding. The extent of DNA damage was measured using neutral comet assay. HKBA was further evaluated for its effect on DNA cell cycle and mitochondria where it was found to arrest cells in G(2)/M phase and also induced loss of mitochondrial membrane potential. These events were associated with increased expression of cytosolic cytochrome c and cleavage of PARP. Target based studies showed that HKBA inhibited the enzymatic activity of topoisomerases I and II at low doses than that of PKBA. In vivo studies also revealed a low dose inhibitory effect of HKBA on ascitic and solid murine tumor models.
Eur J Pharmacol. 2011 Oct;668(3):390-400.
PMID: 21821018 [PubMed - indexed for MEDLINE]
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| 149. |
A novel cyano derivative of 11-keto-β-boswellic acid causes apoptotic death by disrupting PI3K/AKT/Hsp-90 cascade, mitochondrial integrity, and other cell survival signaling events in HL-60 cells.
Khan S, Kaur R, Shah BA, Malik F, Kumar A, Bhushan S, Jain SK, Taneja SC, Singh J
Intervention of apoptosis is a promising strategy for discovery of novel anti-cancer therapeutics. In this study, we examined the ability of a novel cyano derivative of 11-keto-β-boswellic acid, that is, butyl 2-cyano-3,11-dioxours-1,12-dien-24-oate (BCDD) to induce apoptosis in cancer cells. BCDD inhibited cell proliferation with 48 h IC(50) of 0.67 µM in HL-60, 1 µM in Molt4, and 1.5 µM in THP1 cells. The mechanism of cell death was investigated in HL-60 cells where it caused apoptosis by acting against several potential apoptosis suppressive targets. It inhibited phosphatidylinositol-3-kinase (PI3K)/AKT activity, NF-κB, Hsp-90, and survivin which may enhance the sensitivity of cells to apoptosis. Also, BCDD decreased the activity of Bid and Bax in cytosol, caused ΔΨ(mt) loss, releasing pro-apoptotic cytochrome c, SMAC/DIABLO leading to caspase-9-mediated down stream activation of caspase-3, ICAD, and PARP1 cleavage. Translocation of apoptotis-inducing factor (AIF) from mitochondria to the nucleus indicated some caspases-independent apoptosis. Though it upregulated DR-5 and caspase-8, the caspase inhibitor yet had no effect on apoptosis as against 75% inhibition by caspase-9 inhibitor. Attempts were made to examine any acclaimed role of AIF in the activation of caspase-8 using siRNA where it had no effect on caspase-8 activity while the Bax-siRNA inhibited caspase-3 activation suggesting predominance of intrinsic signaling. Our studies thus demonstrated that BCDD exerts multi-focal action in cancer cells while it required 10-fold higher the concentration to produce cytotoxicity in normal human PBMC and gingival cell line, and therefore, may find usefulness in the management of human leukemia.
Mol Carcinog. 2012 Sep;51(9):679-95.
PMID: 21751262 [PubMed - indexed for MEDLINE]
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| 150. |
Boswellic acid inhibits growth and metastasis of human colorectal cancer in orthotopic mouse model by downregulating inflammatory, proliferative, invasive and angiogenic biomarkers.
Yadav VR, Prasad S, Sung B, Gelovani JG, Guha S, Krishnan S, Aggarwal BB
Numerous cancer therapeutics were originally identified from natural products used in traditional medicine. One such agent is acetyl-11-keto-beta-boswellic acid (AKBA), derived from the gum resin of the Boswellia serrata known as Salai guggal or Indian frankincense. Traditionally, it has been used in Ayurvedic medicine to treat proinflammatory conditions. In this report, we hypothesized that AKBA can affect the growth and metastasis of colorectal cancer (CRC) in orthotopically implanted tumors in nude mice. We found that the oral administration of AKBA (50-200 mg/kg) dose-dependently inhibited the growth of CRC tumors in mice, resulting in decrease in tumor volumes than those seen in vehicle-treated mice without significant decreases in body weight. In addition, we observed that AKBA was highly effective in suppressing ascites and distant metastasis to the liver, lungs and spleen in orthotopically implanted tumors in nude mice. When examined for the mechanism, we found that markers of tumor proliferation index Ki-67 and the microvessel density cluster of differentiation (CD31) were significantly downregulated by AKBA treatment. We also found that AKBA significantly suppressed nuclear factor-κB (NF-κB) activation in the tumor tissue and expression of proinflammatory (cyclooxygenase-2), tumor survival (bcl-2, bcl-xL, inhibitor of apoptosis (IAP-1) and survivin), proliferative (cyclin D1), invasive (intercellular adhesion molecule 1 and matrix metalloproteinase-9) and angiogenic C-X-C (CXC) receptor 4 and vascular endothelial growth factor) biomarkers. When examined for serum and tissue levels of AKBA, a dose-dependent increase in the levels of the drug was detected, indicating its bioavailability. Thus, our findings suggest that this boswellic acid analog can inhibit the growth and metastasis of human CRC in vivo through downregulation of cancer-associated biomarkers.
Int J Cancer. 2012 May;130(9):2176-84.
PMID: 21702037 [PubMed - indexed for MEDLINE]
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| 151. |
Growth inhibitory, apoptotic and anti-inflammatory activities displayed by a novel modified triterpenoid, cyano enone of methyl boswellates.
Ravanan P, Singh SK, Rao GS, Kondaiah P
Triterpenoids are pentacyclic secondary metabolites present in many terrestrial plants. Natural triterpenoids have been reported to exhibit anti-inflammatory and anti-carcinogenic activities. Here, we show that modifications of ring A of boswellic acid (2 cyano, 3 enone) resulted in a highly active growth inhibitory, anti-inflammatory, prodifferentiative and anti-tumour triterpenoid compound called cyano enone of methyl boswellates (CEMB). This compound showed cytotoxic activity on a number of cancer cell lines with IC₅₀ ranging from 0.2 to 0.6 μM. CEMB inhibits DNA synthesis and induces apoptosis in A549 cell line at 0.25 μM and 1 μM concentrations, respectively. CEMB induces adipogenic differentiation in 3T3-L1 cells at a concentration of 0.1 μM. Finally, administration of CEMB intra-tumourally significantly inhibited the growth of C6 glioma tumour xenograft in immuno-compromised mice. Collectively, these results suggest that CEMB is a very potent anti-tumour compound.
J Biosci. 2011 Jun;36(2):297-307.
PMID: 21654084 [PubMed - indexed for MEDLINE]
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| 152. |
Antitumor properties of Boswellic acid against Ehrlich ascites cells bearing mouse.
Agrawal SS, Saraswati S, Mathur R, Pandey M
Boswellic acid (BA), a triterpene, isolated from Boswellia serrata (Burseraceae) has been found to possess potent anti-inflammatory and anti-cancer activity. The present study aimed at exploring the possible role of BA on ascites and solid Ehrlich tumor. Ascitic tumor development was evaluated 14 d after tumor implantation by quantification of the ascitic fluid volume whereas solid tumor was evaluated after 30 d tumor implantation by H&E and IHC. The i.p. administration of BA significantly inhibited ascitic and solid Ehrlich tumor model. This inhibition was observed with reduced ascitic volume, solid tumor volume and body weight when compared to control mice. The treatments also increased the survival of tumor-bearing mice. VEGF and TNF- α levels were decreased, whereas the IL-12 levels were increased with BA treatment at 25mg/kg. Further, results on decrease in the peritoneal angiogenesis and microvessel density showed the anti-angiogenic potential. Microscopic examination of tumors revealed that in BA-treated groups the expression of Bax and caspase 3 increased, suggesting drug induced tumor cell apoptosis through activating the pro-apoptotic bcl-2 family and caspase-3. The present study sheds light on the potent antitumor property of the boswellic acid and can be extended further to develop therapeutic protocols for treatment of cancer.
Food Chem Toxicol. 2011 Sep;49(9):1924-34.
PMID: 21513768 [PubMed - indexed for MEDLINE]
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| 153. |
Acetyl-11-keto-β-boswellic acid suppresses invasion of pancreatic cancer cells through the downregulation of CXCR4 chemokine receptor expression.
Park B, Sung B, Yadav VR, Cho SG, Liu M, Aggarwal BB
Ninety percent of cancer-mediated deaths are due to metastasis of the tumor; however, the mechanisms controlling metastasis remain poorly understood. Thus, no therapy targeting this process has yet been approved. Chemokines and their receptors are mediators of chronic inflammation and have been linked to the metastasis of numerous cancers. More recently, the Cysteine X Cysteine (CXC) chemokine receptor 4 (CXCR4) has emerged as a key mediator of tumor metastasis; therefore, identification of inhibitors of this receptor has the potential to abrogate metastasis. In this report, we demonstrate that acetyl-11-keto-β-boswellic acid (AKBA), a component of the therapeutic plant Boswellia serrata, can downregulate CXCR4 expression in pancreatic cancer cells. The reduction in CXCR4 induced by this terpenoid was found to be cell-type specific, as its expression was also abrogated in leukemia, myeloma and breast cancer cell lines. Neither proteasome inhibitors nor lysosomal stabilization could prevent the AKBA-induced reduction in CXCR4 expression. This downregulation occurred at the transcriptional level. Suppression of CXCR4 by AKBA was accompanied by the inhibition of pancreatic cancer cell invasion, which is induced by CXCL12, the ligand for CXCR4. In addition, abrogation of the expression of chemokine receptor by AKBA was found in human pancreatic tissues from orthotopic animal model. AKBA also abolished breast tumor cell invasion, and this effect correlated with the disappearance of both the CXCR4 messenger RNA and CXCR4 protein. Overall, our results show that AKBA is a novel inhibitor of CXCR4 expression and, thus, has the potential to suppress the invasion and metastasis of cancer cells.
Int J Cancer. 2011 Jul;129(1):23-33.
PMID: 21448932 [PubMed - indexed for MEDLINE]
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| 154. |
A cyano analogue of boswellic acid induces crosstalk between p53/PUMA/Bax and telomerase that stages the human papillomavirus type 18 positive HeLa cells to apoptotic death.
Khan S, Chib R, Shah BA, Wani ZA, Dhar N, Mondhe DM, Lattoo S, Jain SK, Taneja SC, Singh J
The p53 tumor suppressor pathway is disrupted by human papillomavirus (HPV) in over 90% of cervical cancers. HPV E6 protein promotes the degradation of p53 thereby inhibiting its stabilization and activation. This study demonstrates that treatment with a novel cyano derivative of 11-keto-β-boswellic acid, i.e. butyl 2-cyano-3, 11-dioxours-1,12-dien-24-oate (BCDD) reduced the viral E6 mRNA expression and lead to the accumulation of transcriptionally active p53 in the nucleus of HPV18 HeLa cells following DNA damage. Western blot analysis showed that BCDD robustly up regulated time-dependent expression of p53/PUMA/p21 whereas it deprived cells essentially of p-AKT and NF-κB cell survival signalling cascade. BCDD appeared to gear up PUMA activation through p53 pathway and that both p53 and p21 translocated heavily into the nucleus. Simultaneously, it inhibited anti-apoptotic Bcl-2, augumented Drp-1 expression, disrupted mitochondrial functions causing the activation of proapoptotic proteins and caspases activation. Additionally, BCDD inhibited telomerase expression that's likely to result in a marked reduction of the tumorigenic potential of high-grade cervical cancers. Consequently BCDD caused apoptotic death in cervical cancer cells as evidenced by DNA fragmentation and PARP-cleavage. Further, BCDD did not affect the extrinsic signalling transduction pathway as depicted by its null effect on caspase-8. The in vivo anticancer activity of BCDD was investigated in Ehrlich Ascites carcinoma model where it exhibited tumor regression by 48% at 30 mg/kg, i.p., in mice. These findings indicated that BCDD is a potential candidate that may be found useful in the management of cervical cancer.
Eur J Pharmacol. 2011 Jun;660(2-3):241-8.
PMID: 21440536 [PubMed - indexed for MEDLINE]
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| 155. |
A comparative study of proapoptotic potential of cyano analogues of boswellic acid and 11-keto-boswellic acid.
Kaur R, Khan S, Chib R, Kaur T, Sharma PR, Singh J, Shah BA, Taneja SC
Semi-synthetic analogues of β-boswellic acid (BA) and 11-keto-β-boswellic acid (KBA) were comparatively evaluated for in vitro cytotoxicity against human myeloid leukaemia (HL-60) and human cervical carcinoma (HeLa) cells. 2-Cyano analogues of both the triterpenes were observed to have significant cytotoxicity against both the cells, displaying cytotoxicity in HL-60 cells at low concentrations. Further investigations suggested the proapoptotic potential associated with the two molecules to induce cytotoxicity in HL-60 cells, where one of them showed early proapoptotic effect as evidenced by several biological end-points of the apoptosis such as annexinV binding, DNA fragmentation and increase in sub-G0 DNA fraction and apoptotic bodies formation (Hoechst 33258 staining and SEM studies).
Eur J Med Chem. 2011 Apr;46(4):1356-66.
PMID: 21334793 [PubMed - indexed for MEDLINE]
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| 156. |
[Effect of acetyl-11-keto-β-boswellic acid on proliferation, apoptosis and cell cycle of human acute myeloid leukemia cell line HL-60].
Yuan XY, Li YH, Qi ZH, Peng MY, Wan Z, Wang GP, Chen FP
The aim of this study was to investigate the effect of 3-O-acetyl-11-keto-β-boswellic acid (AKBA) on the proliferation, apoptosis and cell cycle of human acute myeloid leukemia (AML) cell line HL-60. HL-60 cells were treated by AKBA at various concentrations. The inhibitory effects of AKBA on the proliferation of HL-60 were analyzed by MTT assay. Morphologic changes of HL-60 cells were observed by fluorescence microscopy with Hochest33342 staining. Cell apoptosis rate was determined by flow cytometry with Annexin-V-FITC/PI double staining. The cell cycle was measured by flow cytometry with PI staining. The results showed that AKBA inhibited the proliferation of HL-60 and the apoptosis rate of HL-60 cells was gradually enhanced when AKBA dose increased. AKBA changed the cell cycle of HL-60, resulting in cell increase at G(1) phase and decrease at S phase. It is concluded that the AKBA has anti-proliferation and apoptosis-inducing effects on HL-60 cells, that seems a promising therapeutical approach for AML.
Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2010 Dec;18(6):1440-4.
PMID: 21176347 [PubMed - indexed for MEDLINE]
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| 157. |
[Acetyl-11-keto-beta-boswellic acid and arsenic trioxide regulate the productions and activities of matrix metalloproteinases in human skin fibroblasts and human leukemia cell line THP-1].
Liang YH, Li P, Zhao JX, Liu X, Huang QF
OBJECTIVE: In order to reveal the treatment mechanism of Chinese medicine with the effect of activating blood and resolving putridity, we selected acetyl-11-keto-beta-boswellic acid (AKBA) and arsenic trioxide (ATO), the main monomeric components of frankincense and arsenolite which are two most commonly used Chinese medicine with effect of activating blood and resolving putridity. We combined AKBA and ATO as a compound, and explored its regulatory role in productions and activities of matrix metalloproteinase (MMP)-1, MMP-2 and MMP-9 in human skin fibroblasts (HSFbs) and human acute monocytic leukemia cell line THP-1 in inflammatory state.
METHODS: In order to simulate the inflammatory micro-environment of chronic wounds, we established 3 cell models: HSFb model activated by tumor necrosis factor-alpha (TNF-α), THP-1 cell model activated by phorbol-12-myristate-13-acetate (PMA) and HSFb-THP-1 cell coculture system. AKBA and ATO were cocultured with these cell models. Enzyme-linked immunosorbent assay (ELISA), gelatin zymography assay and reverse transcription-polymerase chain reaction (RT-PCR) were used to test the secretions, activities and mRNA expressions of MMP-1, MMP-2 and MMP-9. In the study of the regulatory mechanism of AKBA and ATO on MMPs, AKBA and ATO were cocultured with the cell models. ELISA was used to test the secretions of TNF-α and interleukin-1beta (IL-β) and Western blot was used to test the phosphorylation levels of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and p38 mitogen-activated proteinkinase (p38MAPK).
RESULTS: Compound of AKBA and ATO inhibited MMP-1, MMP-2 and MMP-9 mRNA expressions, secretions and activities respectively in HSFbs and THP-1 cells in inflammatory state (P<0.05, P<0.01). Also compound of AKBA and ATO inhibited secretions of TNF-α and IL-1β in THP-1 cells and cell coculture system (P<0.01). It also decreased the phosphorylation of ERK1/2 and p38 MAPK in HSFbs and THP-1 cells (P<0.05, P<0.01).
CONCLUSION: The combined use of AKBA and ATO which in line with the rule of activating blood and resolving putridity inhibits fibroblasts and inflammatory cells in producing MMPs in inflammatory state through inhibiting the release of inflammatory factors and MAPK cascade pathway.
Zhong Xi Yi Jie He Xue Bao. 2010 Nov;8(11):1060-9.
PMID: 21078271 [PubMed - indexed for MEDLINE]
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| 158. |
A propionyloxy derivative of 11-keto-β-boswellic acid induces apoptosis in HL-60 cells mediated through topoisomerase I & II inhibition.
Chashoo G, Singh SK, Sharma PR, Mondhe DM, Hamid A, Saxena A, Andotra SS, Shah BA, Qazi NA, Taneja SC, Saxena AK
Boswellic acids have invariably been reported for their antiproliferative potential in various cell systems. In the present study the growth inhibitory effect of propionyloxy derivative of 11-keto-β-boswellic acid (PKBA; a semisynthetic analogue of 11-keto-β-boswellic acid) on HL-60 promyelocytic leukemia cells is being reported for the first time. In the preliminary studies, in vitro cytotoxicity of PKBA was investigated against eight human cancer cell lines viz., IMR-32, SF-295 (both neuroblastoma), PC-3 (prostate), Colo-205 (colon), MCF-7 (breast), OVCAR-5 (ovary), HL-60, Molt-4 (both leukemia) and their respective IC(50) values were found to be 5.95, 7.11, 15.2, 14.5, 15, 15.9, 8.7 & 9.5μg/ml, respectively. For determining the mechanism of cell death in HL-60 cells, PKBA was subjected to different mechanistic studies. DNA relaxation assay of PKBA revealed inhibition of both topoisomerases I & II. The fragmentation analysis of DNA revealed typical ladders indicating the cytotoxic effect to be mediated by induction of apoptosis. The morphologic studies of PKBA showed the presence of true apoptotic bodies. Apoptosis was confirmed further by flow-cytometric detection of sub-G(1) peaks and enhanced annexin-V-FITC binding of the cells. The activation of apoptotic cascade by PKBA in HL-60 cells was found to be associated with the loss of mitochondrial membrane potential, release of cytochrome c, activation of initiator and executioner caspases and cleavage of poly ADP ribose polymerase (PARP). In vivo studies of PKBA revealed anti-tumoral activity against both ascitic and solid murine tumor models. These studies thus demonstrate PKBA to induce apoptosis in HL-60 cells due to the inhibition of topoisomerases I and II.
Chem Biol Interact. 2011 Jan;189(1-2):60-71.
PMID: 21056033 [PubMed - indexed for MEDLINE]
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| 159. |
Synthesis of an antitumor active endoperoxide from 11-keto-beta-boswellic acid.
Csuk R, Niesen-Barthel A, Barthel A, Kluge R, Ströhl D
An endoperoxide was synthesized starting from 11-keto-beta-boswellic acid and screened for antitumor activity in a panel of 15 human cancer cell lines by an SRB assay. The compound induces apoptosis and shows an average IC(50) value of 0.4-4.5 microM.
Eur J Med Chem. 2010 Sep;45(9):3840-3.
PMID: 20538386 [PubMed - indexed for MEDLINE]
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| 160. |
Isolation of hypoxia-inducible factor 1 (HIF-1) inhibitors from frankincense using a molecularly imprinted polymer.
Lakka A, Mylonis I, Bonanou S, Simos G, Tsakalof A
Hypoxia-Inducible Factor 1 (HIF-1), a transcriptional activator, is highly involved in the pathology of cancer. Inhibition of HIF-1 retards tumor growth and enhances treatment efficiency when used in combination with chemo- or radiation therapy. The recent validation of HIF-1 as an important drug target in cancer treatment has stimulated efforts to identify and isolate natural or synthetic HIF-1 inhibitors. In the present study, quercetin, a known inhibitor of HIF-1, was imprinted in a polymer matrix in order to prepare a Molecularly Imprinted Polymer (MIP), which was subsequently used for the selective isolation of new inhibitors from frankincense, a gum resin used as anticancer remedy in traditional medicine. The frankincense components isolated by Solid Phase Extraction on MIP (MIP-SPE), efficiently inhibited the transcriptional activity of HIF-1 and decreased the protein levels of HIF-1α, the regulated subunit of HIF-1. The selective retention of acetyl 11-ketoboswellic acid (AKBA, one of the main bioactive components of frankincense) by MIP led to the revealing of its inhibitory activity on the HIF-1 signaling pathway. AKBA was selectively retained by SPE on the quercetin imprinted polymer, with an imprinting effect of 8.1 ± 4.6. Overall, this study demonstrates the potential of MIP application in the screening, recognition and isolation of new bioactive compounds that aim selected molecular targets, a potential that has been poorly appreciated until.
Invest New Drugs. 2011 Oct;29(5):1081-9.
PMID: 20437079 [PubMed - indexed for MEDLINE]
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| 161. |
[Cembrane diterpenes in olibanum].
Wang F, Li Z, Liu T, Hua H
OBJECTIVE: To study the constituents in the chloroform extract of olibanum and their antitumor activities.
METHOD: The compounds were isolated by chromatographic methods and their structures were identified on the basis of spectroscopic methods and X-ray diffraction. The antiproliferative effect of the compounds in human leukemia HL-60 cells was tested by viable cell counting.
RESULT: Four cembrane diterpenes were isolated and identified as incensole-oxide (1), acetyl incensole-oxide (2), incensole (3), and acetyl incensole (4).
CONCLUSION: Compounds 2 and 4 were isolated from the genus Boswellia for the first time. Compound 4 showed growth inhibitory effect against human leukemia HL-60 cell lines with IG50 value of (16.3 +/- 3.4) micromol x L(-1).
Zhongguo Zhong Yao Za Zhi. 2009 Oct;34(19):2477-80.
PMID: 20067017 [PubMed - indexed for MEDLINE]
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| 162. |
Tirucallic acids are novel pleckstrin homology domain-dependent Akt inhibitors inducing apoptosis in prostate cancer cells.
Estrada AC, Syrovets T, Pitterle K, Lunov O, Büchele B, Schimana-Pfeifer J, Schmidt T, Morad SA, Simmet T
Activation of the serine/threonine kinase Akt is associated with aggressive clinical behavior of prostate cancer. We found that the human prostate cancer cell lines LNCaP and PC-3 express predominantly Akt1 and Akt2. Selective down-regulation of Akt1, but not Akt2, by short-hairpin RNA reduced the viability of prostate cancer cells. In addition, structurally different Akt inhibitors were cytotoxic for the prostate cancer cells, confirming that the Akt pathway is indispensable for their viability. We have purified the tetracyclic triterpenoids 3-oxo-tirucallic acid, 3-alpha-acetoxy-tirucallic acid, and 3-beta-acetoxy-tirucallic acid from the oleogum resin of Boswellia carterii to chemical homogeneity. The acetoxy-derivatives in particular potently inhibited the activities of human recombinant Akt1 and Akt2 and of constitutively active Akt immunoprecipitated from PC-3 cells, whereas inhibitor of nuclear factor-kappaB kinases remained unaffected. Docking data indicated that these tetracyclic triterpenoids form hydrogen bonds within the phosphatidylinositol binding pocket of the Akt pleckstrin homology domain. Accordingly, 3-beta-acetoxy-tirucallic acid did not inhibit the activity of Akt1 lacking the pleckstrin homology domain. In the prostate cancer cell lines investigated, these compounds inhibited the phosphorylation of cellular Akt and the Akt signaling pathways, including glycogen synthase kinase-3beta and BAD phosphorylation, nuclear accumulation of p65, the androgen receptor, beta-catenin, and c-Myc. These events culminated in the induction of apoptosis in prostate cancer, but not in nontumorigenic cells. The tirucallic acid derivatives inhibited proliferation and induced apoptosis in tumors xenografted onto chick chorioallantoic membranes and decreased the growth of pre-established prostate tumors in nude mice without overt systemic toxicity. Thus, tirucallic acid derivatives represent a new class of Akt inhibitors with antitumor properties.
Mol Pharmacol. 2010 Mar;77(3):378-87.
PMID: 20018812 [PubMed - indexed for MEDLINE]
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| 163. |
Boswellic acid inhibits expression of acid sphingomyelinase in intestinal cells.
Zhang Y, Duan RD
BACKGROUND: Boswellic acid is a type of triterpenoids with antiinflammatory and antiproliferative properties. Sphingomyelin metabolism generates multiple lipid signals affecting cell proliferation, inflammation, and apoptosis. Upregulation of acid sphingomyelinase (SMase) has been found in several inflammation-related diseases such as inflammatory bowel diseases, atherosclerosis, and diabetes.
METHODS: The present study is to examine the effect of 3-acetyl-11-keto-beta-boswellic acids (AKBA), a potent boswellic acid, on acid SMase activity and expression in intestinal cells. Both transformed Caco-2 cells and non-transformed Int407 cells were incubated with AKBA. After incubation, the change of acid SMase activity was assayed biochemically, the enzyme protein was examined by Western blot, and acid SMase mRNA was quantified by qPCR.
RESULTS: We found that AKBA decreased acid SMase activity in both intestinal cell lines in dose and time dependent manners without affecting the secretion of the enzyme to the cell culture medium. The effect of AKBA was more effective in the fetal bovine serum-free culture medium. Among different types of boswellic acid, AKBA was the most potent one. The inhibitory effect on acid SMase activity occurred only in the intact cells but not in cell-free extract in the test tubes. At low concentration, AKBA only decreased the acid SMase activity but not the quantity of the enzyme protein. However, at high concentration, AKBA decreased both the mass of acid SMase protein and the mRNA levels of acid SMase in the cells, as demonstrated by Western blot and qPCR, respectively. Under the concentrations decreasing acid SMase activity, AKBA significantly inhibited cell proliferation.
CONCLUSION: We identified a novel inhibitory effect of boswellic acids on acid SMase expression, which may have implications in human diseases and health.
Lipids Health Dis. 2009 Dec;8():51.
PMID: 19951413 [PubMed - indexed for MEDLINE]
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| 164. |
LY294002 enhances boswellic acid-induced apoptosis in colon cancer cells.
Liu JJ, Duan RD
BACKGROUND: Boswellic acids, a type of pentacyclic triterpenoids, have been shown to induce apoptosis in colon cancer cells. The phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) pathway is crucial for cell proliferation and survival. Whether the apoptotic effects of boswellic acid could be affected by inhibition of PI3K/Akt pathway was examined.
MATERIALS AND METHODS: Colon cancer HT29 cells were treated with 3-acetyl-11-keto-beta boswellic acid AKBA in the absence and presence of LY294002 or Wortmanin, inhibitors of PI3K. Apoptosis was determined by flow cytometry and caspase assay. The activation of Akt was examined by Western blot.
RESULTS: AKBA at 30 microM only slightly induced apoptosis. Preincubation of the cells with LY294002 or wortmannin significantly enhanced the AKBA-induced apoptosis up to 20-fold. Further study showed that at the doses used, AKBA induced phosphorylation of Akt at both Ser473 and Thr308 positions, indicating an activation of the PI3K/Akt pathway.
CONCLUSION: AKBA may activate the PI3K/Akt pathway and inhibition of the PI3K pathway significantly enhances AKBA-induced apoptosis.
Anticancer Res. 2009 Aug;29(8):2987-91.
PMID: 19661305 [PubMed - indexed for MEDLINE]
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| 165. |
Acetyl-11-keto-beta-boswellic acid inhibits prostate tumor growth by suppressing vascular endothelial growth factor receptor 2-mediated angiogenesis.
Pang X, Yi Z, Zhang X, Sung B, Qu W, Lian X, Aggarwal BB, Liu M
The role of angiogenesis in tumor growth and metastasis is well established. Identification of a small molecule that blocks tumor angiogenesis and is safe and affordable has been a challenge in drug development. In this study, we showed that acetyl-11-keto-beta-boswellic acid (AKBA), an active component from an Ayurvedic medicinal plant (Boswellia serrata), could strongly inhibit tumor angiogenesis. AKBA suppressed tumor growth in the human prostate tumor xenograft mice treated daily (10 mg/kg AKBA) after solid tumors reached approximately 100 mm(3) (n = 5). The inhibitory effect of AKBA on tumor growth was well correlated with suppression of angiogenesis. When examined for the molecular mechanism, we found that AKBA significantly inhibited blood vessel formation in the Matrigel plug assay in mice and effectively suppressed vascular endothelial growth factor (VEGF)-induced microvessel sprouting in rat aortic ring assay ex vivo. Furthermore, AKBA inhibited VEGF-induced cell proliferation, chemotactic motility, and the formation of capillary-like structures from primary cultured human umbilical vascular endothelial cells in a dose-dependent manner. Western blot analysis and in vitro kinase assay revealed that AKBA suppressed VEGF-induced phosphorylation of VEGF receptor 2 (VEGFR2) kinase (KDR/Flk-1) with IC(50) of 1.68 micromol/L. Specifically, AKBA suppressed the downstream protein kinases of VEGFR2, including Src family kinase, focal adhesion kinase, extracellular signal-related kinase, AKT, mammalian target of rapamycin, and ribosomal protein S6 kinase. Our findings suggest that AKBA potently inhibits human prostate tumor growth through inhibition of angiogenesis induced by VEGFR2 signaling pathways.
Cancer Res. 2009 Jul;69(14):5893-900.
PMID: 19567671 [PubMed - indexed for MEDLINE]
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| 166. |
Activation of p53/p21/PUMA alliance and disruption of PI-3/Akt in multimodal targeting of apoptotic signaling cascades in cervical cancer cells by a pentacyclic triterpenediol from Boswellia serrata.
Bhushan S, Malik F, Kumar A, Isher HK, Kaur IP, Taneja SC, Singh J
Cervical carcinoma is a growing menace to women health worldwide. This study reports the apoptotic cell death in human cervical cancer HeLa and SiHa cells by a pentacyclic triterpenediol (TPD) from Boswellia serrata by a mechanism different from reported in HL-60 cells. It caused oxidative stress by early generation of nitric oxide and reactive oxygen species that robustly up regulated time-dependent expression of p53/p21/PUMA while conversely abrogating phosphatidylinositol-3-kinase (PI3K)/Akt pathways in parallel. TPD also decreased the expression of PI3K/pAkt, ERK1/2, NF-kappaB/Akt signaling cascades which coordinately contribute to cancer cell survival through these distinct pathways. The tumor suppressor p53 pathway predominantly activated by TPD further up-regulated PUMA, which concomitantly decreased the Bcl-2 level, caused mitochondrial membrane potential loss with attendant translocation of Bax and drp1 to mitochondria and release of pro-apoptotic factors such as cytochrome c and Smac/Diablo to cytosol leading to caspases-3 and -9 activation. In addition both the phospho-p53 and p21 were found to accumulate heavily in the nuclear fraction with attendant decrease in topoisomarase II and survivin levels. On the contrary, TPD did not affect the extrinsic signaling transduction pathway effectively through apical death receptors. Interestingly, N-acetyl cysteine, ascorbate and s-methylisothiourea (sMIT) rescued cells significantly from TPD induced DNA damage and caspases activation. TPD may thus find usefulness in managing and treating cervical cancer.
Mol Carcinog. 2009 Dec;48(12):1093-108.
PMID: 19544329 [PubMed - indexed for MEDLINE]
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| 167. |
Studies of the in vitro anticancer, antimicrobial and antioxidant potentials of selected Yemeni medicinal plants from the island Soqotra.
Mothana RA, Lindequist U, Gruenert R, Bednarski PJ
BACKGROUND: Recent years have witnessed that there is a revival of interest in drug discovery from medicinal plants for the maintenance of health in all parts of the world. The aim of this work was to investigate 26 plants belonging to 17 families collected from a unique place in Yemen (Soqotra Island) for their in vitro anticancer, antimicrobial and antioxidant activities.
METHODS: The 26 plants were extracted with methanol and hot water to yield 52 extracts. Evaluation for in vitro anticancer activity was done against three human cancer cell lines (A-427, 5637 and MCF-7) by using an established microtiter plate assay based on cellular staining with crystal violet. Antimicrobial activity was tested against three Gram-positive bacteria, two Gram-negative bacteria, one yeast species and three multiresistant Staphylococcus strains by using an agar diffusion method and the determination of MIC against three Gram-positive bacteria with the broth micro-dilution assay. Antioxidant activity was investigated by measuring the scavenging activity of the DPPH radical. Moreover, a phytochemical screening of the methanolic extracts was done.
RESULTS: Notable cancer cell growth inhibition was observed for extracts from Ballochia atro-virgata, Eureiandra balfourii and Hypoestes pubescens, with IC50 values ranging between 0.8 and 8.2 microg/ml. The methanol extracts of Acanthospermum hispidum, Boswellia dioscorides, Boswellia socotrana, Commiphora ornifolia and Euphorbia socotrana also showed noticeable antiproliferative potency with IC50 values < 50 microg/ml. The greatest antimicrobial activity was exhibited by extracts from Acacia pennivenia, Boswellia dioscorides, Boswellia socotrana, Commiphora ornifolia, Euclea divinorum, Euphorbia socotrana, Leucas samhaensis, Leucas virgata, Rhus thyrsiflora, and Teucrium sokotranum with inhibition zones > 15 mm and MIC values
CONCLUSION: Our results show once again that medicinal plants can be promising sources of natural products with potential anticancer, antimicrobial and antioxidative activity. The results will guide the selection of some plant species for further pharmacological and phytochemical investigations.
BMC Complement Altern Med. 2009 Mar;9():7.
PMID: 19320966 [PubMed - indexed for MEDLINE]
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| 168. |
Frankincense oil derived from Boswellia carteri induces tumor cell specific cytotoxicity.
Frank MB, Yang Q, Osban J, Azzarello JT, Saban MR, Saban R, Ashley RA, Welter JC, Fung KM, Lin HK
BACKGROUND: Originating from Africa, India, and the Middle East, frankincense oil has been important both socially and economically as an ingredient in incense and perfumes for thousands of years. Frankincense oil is prepared from aromatic hardened gum resins obtained by tapping Boswellia trees. One of the main components of frankincense oil is boswellic acid, a component known to have anti-neoplastic properties. The goal of this study was to evaluate frankincense oil for its anti-tumor activity and signaling pathways in bladder cancer cells.
METHODS: Frankincense oil-induced cell viability was investigated in human bladder cancer J82 cells and immortalized normal bladder urothelial UROtsa cells. Temporal regulation of frankincense oil-activated gene expression in bladder cancer cells was identified by microarray and bioinformatics analysis.
RESULTS: Within a range of concentration, frankincense oil suppressed cell viability in bladder transitional carcinoma J82 cells but not in UROtsa cells. Comprehensive gene expression analysis confirmed that frankincense oil activates genes that are responsible for cell cycle arrest, cell growth suppression, and apoptosis in J82 cells. However, frankincense oil-induced cell death in J82 cells did not result in DNA fragmentation, a hallmark of apoptosis.
CONCLUSION: Frankincense oil appears to distinguish cancerous from normal bladder cells and suppress cancer cell viability. Microarray and bioinformatics analysis proposed multiple pathways that can be activated by frankincense oil to induce bladder cancer cell death. Frankincense oil might represent an alternative intravesical agent for bladder cancer treatment.
BMC Complement Altern Med. 2009 Mar;9():6.
PMID: 19296830 [PubMed - indexed for MEDLINE]
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| 169. |
Boswellic acid blocks signal transducers and activators of transcription 3 signaling, proliferation, and survival of multiple myeloma via the protein tyrosine phosphatase SHP-1.
Kunnumakkara AB, Nair AS, Sung B, Pandey MK, Aggarwal BB
Activation of signal transducers and activators of transcription-3 (STAT-3) has been linked with survival, proliferation, chemoresistance, and angiogenesis of tumor cells, including human multiple myeloma (MM). Thus, agents that can suppress STAT3 activation have potential as cancer therapeutics. In our search for such agents, we identified acetyl-11-keto-beta-boswellic acid (AKBA), originally isolated from Boswellia serrata. Our results show that AKBA inhibited constitutive STAT3 activation in human MM cells. AKBA suppressed IL-6-induced STAT3 activation, and the inhibition was reversible. The phosphorylation of both Jak 2 and Src, constituents of the STAT3 pathway, was inhibited by AKBA. Interestingly, treatment of cells with pervanadate suppressed the effect of AKBA to inhibit the phosphorylation of STAT3, thus suggesting the involvement of a protein tyrosine phosphatase. We found that AKBA induced Src homology region 2 domain-containing phosphatase 1 (SHP-1), which may account for its role in dephosphorylation of STAT3. Moreover, deletion of the SHP-1 gene by small interfering RNA abolished the ability of AKBA to inhibit STAT3 activation. The inhibition of STAT3 activation by AKBA led to the suppression of gene products involved in proliferation (cyclin D1), survival (Bcl-2, Bcl-xL, and Mcl-1), and angiogenesis (VEGF). This effect correlated with the inhibition of proliferation and apoptosis in MM cells. Consistent with these results, overexpression of constitutive active STAT3 significantly reduced the AKBA-induced apoptosis. Overall, our results suggest that AKBA is a novel inhibitor of STAT3 activation and has potential in the treatment of cancer.
Mol Cancer Res. 2009 Jan;7(1):118-28.
PMID: 19147543 [PubMed - indexed for MEDLINE]
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| 170. |
Chemical modifications of natural triterpenes - glycyrrhetinic and boswellic acids: evaluation of their biological activity.
Subba Rao GS, Kondaiah P, Singh SK, Ravanan P, Sporn MB
Synthetic analogues of naturally occurring triterpenoids; glycyrrhetinic acid, arjunolic acid and boswellic acids, by modification of A-ring with a cyano- and enone- functionalities, have been reported. A novel method of synthesis of α-cyanoenones from isoxazoles is reported. Bio-assays using primary mouse macrophages and tumor cell lines indicate potent anti-inflammatory and cytotoxic activities associated with cyanoenones of boswellic acid and glycyrrhetinic acid.
Tetrahedron. 2008 Dec;64(51):11541-11548.
PMID: 20622928 [PubMed - as supplied by publisher]
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| 171. |
Bosellia serrata-induced apoptosis is related with ER stress and calcium release.
Kim HR, Kim MS, Kwon DY, Chae SW, Chae HJ
It has been reported that the gum resin of Boswellia serrata (BS), which has been shown to have antiinflammatory properties, might also have anticancer effects. This study examined the potential of BS as an anticancer agent. The BS extract induces apoptosis in HeLa human cervical carcinoma cells, as confirmed by two apoptosis analyses, Hoechst staining and Annexin V/PI assay. Among the apoptosis pathways, the ER stress-associated mechanism was examined to determine its role in BS-induced apoptosis. The expression of GRP78 and CHOP, which are representatives of the ER stress proteins, and the calcium-binding protein-calpain were determined. The results showed significantly higher levels of both GRP78 and CHOP, and stronger calpain activity in the BS-treated cells than in the control cells. This shows that there is a correlation between ER stress signaling and apoptosis, which suggests the possibility of the BS-ER stress initiator as an anticancer therapeutic agent in human cervical carcinoma.
Genes Nutr. 2008 Feb;2(4):371-4.
PMID: 18850233 [PubMed - as supplied by publisher]
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| 172. |
In vitro screening for the tumoricidal properties of international medicinal herbs.
Mazzio EA, Soliman KF
There is growing use of anticancer complementary and alternative medicines (CAMs) worldwide. The purpose of the current study is to assess a sizeable variety of natural and plant sources of diverse origin, to ascertain prospective research directives for cancer treatment and potential new chemotherapy drug sources. In this study, 374 natural extracts (10 microg/mL-5 mg/mL) were evaluated for dose-dependent tumoricidal effects using immortal neuroblastoma of spontaneous malignant origin. The findings indicate no pattern of tumoricidal effects by diverse plants with similar families/genus under the classes Pinopsida, Equisetopsida, Lycopodiosida, Filicosida, Liliopsida Monocotyledons or Magnoliopsida Dicotyledons. The results indicate that many of the most commonly used CAMs exhibited relatively weak tumoricidal effects including cats claw, astragalus, ginseng, echinacea, mistletoe, milk thistle, slippery elm, cayenne, chamomile, don quai, meadowsweet, motherwort and shepherd's purse. The data demonstrate that the most potent plant extracts were randomly dispersed within the plantae kingdom (LC(50) = 31-490 microg/mL) in order of the lowest LC(50) Dioscorea villosa (Dioscoreaceae) > Sanguinaria canadensis (Papaveraceae) > Dipsacus asper (Dipsacaceae) > Populus balsamifera (Salicaceae) > Boswellia carteri (Burseraceae) > Cyamopsis psoralioides (Fabaceae) > Rhamnus cathartica (Rhamnaceae) > Larrea tridentate (Zygophyllaceae) > Dichroa febrifuga (Hydrangeaceae) > Batschia canescens (Boraginaceae) > Kochia scoparia (Chenopodiaceae) > Solanum xanthocarpum (Solanaceae) > Opoponax chironium (Umbelliferae) > Caulophyllum thalictroides (Berberidaceae) > Dryopteris crassirhizoma (Dryopteridaceae) > Garcinia cambogia (Clusiaceae) > Vitex agnus-castus (Verbenaceae) > Calamus draco (Arecaceae). These findings show tumoricidal effect by extracts of wild yam root, bloodroot, teasel root, bakuchi seed, dichroa root, kanta kari, garcinia fruit, mace, dragons blood and the biblically referenced herbs: balm of gilead bud, frankincense and myrrh gum.
Phytother Res. 2009 Mar;23(3):385-98.
PMID: 18844256 [PubMed - indexed for MEDLINE]
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| 173. |
Inhibitory effect of acetyl-11-keto-beta-boswellic acid on androgen receptor by interference of Sp1 binding activity in prostate cancer cells.
Yuan HQ, Kong F, Wang XL, Young CY, Hu XY, Lou HX
Androgen receptor (AR)-mediated signaling is crucial for the development and progression of prostate cancer (PCa). Naturally occurring phytochemicals that target the AR signaling offer significant protection against this disease. Acetyl-11-keto-beta-boswellic acid (AKBA), a compound isolated from the gum-resin of Boswellia carterii, caused G1-phase cell cycle arrest with an induction of p21(WAF1/CIP1), and a reduction of cyclin D1 as well in prostate cancer cells. AKBA-mediated cellular proliferation inhibition was associated with a decrease of AR expression at mRNA and protein levels. Furthermore, the functional biomarkers used in evaluation of AR transactivity showed suppressions of prostate-specific antigen promoter-dependent and androgen responsive element-dependent luciferase activities. Additionally, down-regulation of an AR short promoter mainly containing a Sp1 binding site suggested the essential role of Sp1 for the reduction of AR expression in cells exposed to AKBA. Interruption effect of AKBA on Sp1 binding activity but not Sp1 protein levels was further confirmed by EMSA and transient transfection with a luciferase reporter driven by three copies of the Sp1 binding site of the AR promoter. Therefore, anti-AR properties ascribed to AKBA suggested that AKBA-containing drugs could be used for the development of novel therapeutic chemicals.
Biochem Pharmacol. 2008 Jun;75(11):2112-21.
PMID: 18430409 [PubMed - indexed for MEDLINE]
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| 174. |
Comparison of the irritation potentials of Boswellia serrata gum resin and of acetyl-11-keto-beta-boswellic acid by in vitro cytotoxicity tests on human skin-derived cell lines.
Burlando B, Parodi A, Volante A, Bassi AM
Indian frankincense is a gum resin from Boswellia serrata of Burseraceae used in Ayurveda and Western medicine for the antinflammatory effects of boswellic acids, particularly 3-O-acetyl-11-keto-beta-boswellic acid (AKBA). We evaluated in vitro cytotoxicities of B. serrata extract and AKBA on differentiated and undifferentiated keratinocytes (HaCaT and NCTC 2544), and foetal dermal fibroblasts (HFFF2), using neutral red uptake (NRU), MTT, and DNA assays. Comparison between NRU and MTT, and between the extract and AKBA, suggested a relatively higher toxicity of both substances on lysosomes respect to mitochondria. Extract cytotoxicity on lysosomes was higher in NCTC and HFFF2 than on the more differentiated HaCaT. DNA assay showed low extract inhibition on HFFF2 proliferation, possibly due to lower growth rate, and a stronger effect on NCTC than on HaCaT, possibly related to higher proapoptotic effect on the less differentiated NCTC, as also suggested by higher AKBA toxicity on NCTC than on HaCaT. In general, gum resin and AKBA toxicities were slightly lower or higher than that of the reference compound SDS. Our in vitro model allowed to compare the sensitivities of different human skin cells to B. serrata, and indicated that the gum resin and AKBA exert moderate to low toxicity on the skin.
Toxicol Lett. 2008 Mar;177(2):144-9.
PMID: 18304763 [PubMed - indexed for MEDLINE]
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| 175. |
Acetyl-keto-beta-boswellic acid induces apoptosis through a death receptor 5-mediated pathway in prostate cancer cells.
Lu M, Xia L, Hua H, Jing Y
Acetyl-keto-beta-boswellic acid (AKBA), a triterpenoid isolated from Boswellia carterri Birdw and Boswellia serrata, has been found to inhibit tumor cell growth and to induce apoptosis. The apoptotic effects and the mechanisms of action of AKBA were studied in LNCaP and PC-3 human prostate cancer cells. AKBA induced apoptosis in both cell lines at concentrations above 10 microg/mL. AKBA-induced apoptosis was correlated with the activation of caspase-3 and caspase-8 as well as with poly(ADP)ribose polymerase (PARP) cleavage. The activation of caspase-8 was correlated with increased levels of death receptor (DR) 5 but not of Fas or DR4. AKBA-induced apoptosis, caspase-8 activation, and PARP cleavage were inhibited by knocking down DR5 using a small hairpin RNA. AKBA treatment increased the levels of CAAT/enhancer binding protein homologous protein (CHOP) and activated a DR5 promoter reporter but did not activate a DR5 promoter reporter with the mutant CHOP binding site. These results suggest that AKBA induces apoptosis in prostate cancer cells through a DR5-mediated pathway, which probably involves the induced expression of CHOP.
Cancer Res. 2008 Feb;68(4):1180-6.
PMID: 18281494 [PubMed - indexed for MEDLINE]
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| 176. |
Cytotoxic and apoptotic activities of novel amino analogues of boswellic acids.
Shah BA, Kumar A, Gupta P, Sharma M, Sethi VK, Saxena AK, Singh J, Qazi GN, Taneja SC
4-Amino analogues prepared from beta-boswellic acid and 11-keto-beta-boswellic acid, wherein the carboxyl group in ursane nucleus was replaced by an amino function via Curtius reaction, displayed improved cytotoxicity than the parent molecules. The same molecules also exhibited apoptotic activity by inducing DNA fragmentation.
Bioorg Med Chem Lett. 2007 Dec;17(23):6411-6.
PMID: 17950603 [PubMed - indexed for MEDLINE]
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| 177. |
A triterpenediol from Boswellia serrata induces apoptosis through both the intrinsic and extrinsic apoptotic pathways in human leukemia HL-60 cells.
Bhushan S, Kumar A, Malik F, Andotra SS, Sethi VK, Kaur IP, Taneja SC, Qazi GN, Singh J
A triterpenediol (TPD) comprising of isomeric mixture of 3alpha, 24-dihydroxyurs-12-ene and 3alpha, 24-dihydroxyolean-12-ene from Boswellia serrata induces apoptosis in cancer cells. An attempt was made in this study to investigate the mechanism of cell death by TPD in human leukemia HL-60 cells. It inhibited cell proliferation with IC50 approximately 12 microg/ml and produced apoptosis as measured by various biological end points e.g. increased sub-G0 DNA fraction, DNA ladder formation, enhanced AnnexinV-FITC binding of the cells. Further, initial events involved massive reactive oxygen species (ROS) and nitric oxide (NO) formation, which were significantly inhibited by their respective inhibitors. Persistent high levels of NO and ROS caused Bcl-2 cleavage and translocation of Bax to mitochondria, which lead to loss of mitochondrial membrane potential (Deltapsim) and release of cytochrome c, AIF, Smac/DIABLO to the cytosol. These events were associated with decreased expression of survivin and ICAD with attendant activation of caspases leading to PARP cleavage. Furthermore, TPD up regulated the expression of cell death receptors DR4 and TNF-R1 level, leading to caspase-8 activation. These studies thus demonstrate that TPD produces oxidative stress in cancer cells that triggers self-demise by ROS and NO regulated activation of both the intrinsic and extrinsic signaling cascades.
Apoptosis. 2007 Oct;12(10):1911-26.
PMID: 17636381 [PubMed - indexed for MEDLINE]
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| 178. |
Effect of acetyl 11-keto beta-boswellic acid on metastatic growth factor responsible for angiogenesis.
Singh SK, Bhusari S, Singh R, Saxena A, Mondhe D, Qazi GN
Basic fibroblast growth factor (bFGF), a metastatic growth factor is known to be one of the promoting factors in the tumor induced angiogenesis. The antiangiogenic activity of acetyl 11-keto beta-boswellic acid was screened against bFGF-induced angiogenesis using in-vivo Matrigel Plug Assay. Histological & colorimetric examination confirmed that numerous blood vessels were present in Matrigel+bFGF group in comparison to Matrigel alone treated mice. Acetyl 11-keto beta-boswellic acids (10 mg/kg/d) inhibited the Matrigel+bFGF-induced angiogenesis significantly (P<0.01) in contrast to anti-inflammatory agent indomethacin (10 mg/kg/d) and alkylating agent cyclophosphamide (10 mg/kg/d).
Vascul Pharmacol. 2007 May;46(5):333-7.
PMID: 17257903 [PubMed - indexed for MEDLINE]
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| 179. |
Characterization of 3alpha-acetyl-11-keto-alpha-boswellic acid, a pentacyclic triterpenoid inducing apoptosis in vitro and in vivo.
Büchele B, Zugmaier W, Estrada A, Genze F, Syrovets T, Paetz C, Schneider B, Simmet T
3Alpha-acetyl-11-keto-alpha-boswellic acid (3alpha-acetoxy-11-oxo-olean-12-en-24-oic acid, 1) was synthesized by a radical-type reaction using bromine and 3alpha-acetyl-alpha-boswellic acid isolated from the oleo-gum-resin of Boswellia carterii. 1D and 2D NMR (COSY, HMBC, ROESY) at 500 MHz were used for shift assignments and structure verification. The compound investigated is present in a herbal preparation extracted from Boswellia serrata oleo-gum-resin, it inhibits the growth of chemotherapy-resistant human PC-3 prostate cancer cells in vitro and induces apoptosis as shown by activation of caspase 3 and the induction of DNA fragmentation. In addition, compound 1 is active IN VIVO as shown by inhibition of proliferation and induction of apoptosis in PC-3 prostate cancer cells xenotransplanted onto the chick chorioallantoic membrane.
Planta Med. 2006 Nov;72(14):1285-9.
PMID: 17022003 [PubMed - indexed for MEDLINE]
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| 180. |
A lipoxygenase inhibitor in breast cancer brain metastases.
Flavin DF
The complication of multiple brain metastases in breast cancer patients is a life threatening condition with limited success following standard therapies. The arachidonate lipoxygenase pathway appears to play a role in brain tumor growth as well as inhibition of apoptosis in in-vitro studies. The down regulation of these arachidonate lipoxygenase growth stimulating products therefore appeared to be a worthwhile consideration for testing in brain metastases not responding to standard therapy. Boswellia serrata, a lipoxygenase inhibitor was applied for this inhibition. Multiple brain metastases were successfully reversed using this method in a breast cancer patient who had not shown improvement after standard therapy. The results suggest a potential new area of therapy for breast cancer patients with brain metastases that may be useful as an adjuvant to our standard therapy.
J Neurooncol. 2007 Mar;82(1):91-3.
PMID: 17001517 [PubMed - indexed for MEDLINE]
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| 181. |
Cancer chemopreventive effects and cytotoxic activities of the triterpene acids from the resin of Boswellia carteri.
Akihisa T, Tabata K, Banno N, Tokuda H, Nishimura R, Nakamura Y, Kimura Y, Yasukawa K, Suzuki T
Fifteen triterpene acids, viz., seven of the beta-boswellic acids (ursane-type) (1-7), two of the alpha-boswellic acids (oleanane-type) (8, 9), two of the lupeolic acids (lupane-type) (10, 11), and four of the tirucallane-type (12-14, 16), and two cembrane-type diterpenes (17, 18), isolated from the MeOH extract of the resin of Boswellia carteri (Burseraceae), together with a triterpene acid 15 (the acetyl derivative of 14), were examined for their inhibitory effects on the induction of Epstein-Barr virus early antigen (EBV-EA) by 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells and on activation of (+/-)-(E)-methyl-2[(E)-hydroxyimino]-5-nitro-6-methoxy-3-hexemide (NOR 1), a nitrogen oxide (NO) donor, and cytotoxic activities against three human neuroblastoma cell lines, IMR-32, NB-39, and SK-N-SH in vitro. On evaluation against the EBV-EA activation induced by TPA, seven compounds, 2, 10, 11, and 13-16, showed potent inhibitory effects on EBV-EA induction. Upon evaluation against activation of NOR 1, five compounds, 7, 13, and 14-16, showed potent inhibitory effects. Further, fifteen compounds, 1-7, 9-11, 13-15, 17, and 18, exhibited potent cytotoxic activities with IC(50) values of 4.1-82.4 muM against all of the three human neuroblastoma cells tested.
Biol Pharm Bull. 2006 Sep;29(9):1976-9.
PMID: 16946522 [PubMed - indexed for MEDLINE]
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| 182. |
Acetyl-keto-beta-boswellic acid inhibits cellular proliferation through a p21-dependent pathway in colon cancer cells.
Liu JJ, Huang B, Hooi SC
1. Although there is increasing evidence showing that boswellic acid might be a potential anticancer agent, the mechanisms involved in its action are unclear. 2. In the present study, we showed that acetyl-keto-beta-boswellic acid (AKBA) inhibited cellular growth in several colon cancer cell lines. Cell cycle analysis by flow cytometry showed that cells were arrested at the G1 phase after AKBA treatment. 3. Further analysis showed that cyclin D1 and E, CDK 2 and 4 and phosphorylated Rb were decreased in AKBA-treated cells while p21 expression was increased. 4. The growth inhibitory effect of AKBA was dependent on p21 but not p53. HCT-116 p53(-/-) cells were sensitized to the apoptotic effect of AKBA, suggesting that p21 may have protected cells against apoptosis by inducing a G1 arrest.5. In conclusion, we have demonstrated that AKBA inhibited cellular growth in colon cancer cells. These findings may have implications to the use of boswellic acids as potential anticancer agents in colon cancer.
Br J Pharmacol. 2006 Aug;148(8):1099-107.
PMID: 16783403 [PubMed - indexed for MEDLINE]
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| 183. |
Boswellic acid acetate induces apoptosis through caspase-mediated pathways in myeloid leukemia cells.
Xia L, Chen D, Han R, Fang Q, Waxman S, Jing Y
The mechanism of the cytotoxic effect of boswellic acid acetate, a 1:1 mixture of alpha-boswellic acid acetate and beta-boswellic acid acetate, isolated from Boswellia carterri Birdw on myeloid leukemia cells was investigated in six human myeloid leukemia cell lines (NB4, SKNO-1, K562, U937, ML-1, and HL-60 cells). Morphologic and DNA fragmentation assays indicated that the cytotoxic effect of boswellic acid acetate was mediated by induction of apoptosis. More than 50% of the cells underwent apoptosis after treatment with 20 mug/mL boswellic acid for 24 hours. This apoptotic process was p53 independent. The levels of apoptosis-related proteins Bcl-2, Bax, and Bcl-XL were not modulated by boswellic acid acetate. Boswellic acid acetate induced Bid cleavage and decreased mitochondrial membrane potential without production of hydrogen peroxide. A general caspase inhibitor (Z-VAD-FMK) and a specific caspase-8 inhibitor II (Z-IETD-FMK) blocked boswellic acid acetate-induced apoptosis. The mRNAs of death receptors 4 and 5 (DR4 and DR5) were induced in leukemia cells undergoing apoptosis after boswellic acid acetate treatment. These data taken together suggest that boswellic acid acetate induces myeloid leukemia cell apoptosis through activation of caspase-8 by induced expression of DR4 and DR5, and that the activated caspase-8 either directly activates caspase-3 by cleavage or indirectly by cleaving Bid, which in turn decreases mitochondria membrane potential.
Mol Cancer Ther. 2005 Mar;4(3):381-8.
PMID: 15767547 [PubMed - indexed for MEDLINE]
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| 184. |
Inhibition of IkappaB kinase activity by acetyl-boswellic acids promotes apoptosis in androgen-independent PC-3 prostate cancer cells in vitro and in vivo.
Syrovets T, Gschwend JE, Büchele B, Laumonnier Y, Zugmaier W, Genze F, Simmet T
Signaling through NF-kappaB has been implicated in the malignant phenotype as well as the chemoresistance of various cancers. Here we show that the natural compounds acetyl-beta-boswellic acid and acetyl-11-keto-beta-boswellic acid (AKbetaBA) inhibit proliferation and elicit cell death in chemoresistant androgen-independent PC-3 prostate cancer cells in vitro and in vivo. Induction of apoptosis was demonstrated in cultured PC-3 cells by several parameters including mitochondrial cytochrome c release and DNA fragmentation. At the molecular level these compounds inhibit constitutively activated NF-kappaB signaling by intercepting the IkappaB kinase (IKK) activity; signaling through the interferon-stimulated response element remained unaffected, suggesting specificity for IKK inhibition. The impaired phosphorylation of p65 and the reduced nuclear translocation of NF-kappaB proteins were associated with down-regulation of the constitutively overexpressed and NF-kappaB-dependent antiapoptotic proteins Bcl-2 and Bcl-x(L). In addition, expression of cyclin D1, a crucial cell cycle regulator, was reduced as well. Down-regulation of IKK by antisense oligodeoxynucleotides confirmed the essential role of IKK inhibition for the proliferation of the PC-3 cells. Both compounds tested were active in vivo, yet AKbetaBA proved to be far superior. Indeed, topical application of water-soluble AKbetaBA-gamma-cyclodextrin on PC-3 tumors xenografted onto chick chorioallantoic membranes induced concentration-dependent inhibition of proliferation as well as apoptosis. Similarly, in nude mice carrying PC-3 tumors, systemic application of AKbetaBA-gamma-cyclodextrin inhibited tumor growth and triggered apoptosis in the absence of detectable systemic toxicity. Thus, AKbetaBA and related compounds acting on IKK might provide a novel approach for the treatment of chemoresistant human tumors such as androgen-independent human prostate cancers.
J Biol Chem. 2005 Feb;280(7):6170-80.
PMID: 15576374 [PubMed - indexed for MEDLINE]
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| 185. |
Ursolic acid inhibits proliferation and stimulates apoptosis in HT29 cells following activation of alkaline sphingomyelinase.
Andersson D, Liu JJ, Nilsson A, Duan RD
BACKGROUND: Ursolic acid (UA) is a plant component with anti-inflammatory and anti-proliferative properties. Its effect on colon cancer is not clear. We studied the anticancer effects of UA on human colon cancer cells.
MATERIALS AND METHODS: HT-29 cells were treated with UA. Cell proliferation was determined by cleavage of WST-1. Apoptosis was assayed by cytosolic DNA-histone complex and caspase activity. Sphingomyelinase and alkaline phosphatase were determined against specific substrates.
RESULTS: UA dose-dependently decreased cell proliferation and induced apoptosis, accompanied by activation of caspase 3, 8 and 9. Its antiproliferative effect was stronger than those of sulindac and camptothecin and its apoptotic effect stronger than those of boswellic acid and sulindac. UA selectively increased the activity of intestinal alkaline sphingomyelinase, which occurred before activation of caspases. UA had no effect on alkaline phosphatase activity.
CONCLUSION: UA has strong anti-proliferative and apoptotic effects on HT-29 cells. The effects may be mediated by alkaline sphingomyelinase activation.
Anticancer Res. 2003;23(4):3317-22.
PMID: 12926069 [PubMed - indexed for MEDLINE]
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| 186. |
Acetyl-11-keto-beta-boswellic acid (AKBA) is cytotoxic for meningioma cells and inhibits phosphorylation of the extracellular-signal regulated kinase 1 and 2.
Park YS, Lee JH, Harwalkar JA, Bondar J, Safayhi H, Golubic M
Acetyl-11-keto-beta-boswellic acid (AKBA) is a naturally occurring pentacyclic triterpene isolated from the gum resin exudate from the stem of the tree Boswellia serrata (frankincense). AKBA has been recently identified as a novel, orally active, non-redox and non-competitive 5-lipoxygenase inhibitor that also inhibits topisomerase I and II in vitro. Because natural pentacyclic triterpenes have an antiproliferative effect against different tumor types, we investigated the effects of AKBA on the proliferation of 11 primary cell cultures established from human surgical specimens of meningiomas, common central nervous system tumors. Treatment of meningioma cells by AKBA revealed a potent cytotoxic activity with half-maximal inhibitory concentrations in the range of 2-8 microM. At similar, physiologically achievable concentrations, AKBA rapidly (within minutes) and potently inhibited the phosphorylation of extracellular signal-regulated kinase 1 and 2 (Erk-1 and Erk-2) in meningioma cells stimulated with platelet-derived growth factor BB. High expression level of 5-LO was detected in primary meningioma cells and surgical specimens by immunoblotting analysis, suggesting the possible role of 5-LO in meningioma tumorigenesis. Considering the critical importance of the Erk-1/2 signal transduction pathway not only in meningiomas but in other human neoplasms, the interruption of signaling through this evolutionarily conserved pathway might be one of the mechanisms by which AKBA induces suppression of proliferation and apoptosis of different tumor types.
Adv Exp Med Biol. 2002;507():387-93.
PMID: 12664615 [PubMed - indexed for MEDLINE]
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| 187. |
Boswellic acid acetate induces differentiation and apoptosis in highly metastatic melanoma and fibrosarcoma cells.
Zhao W, Entschladen F, Liu H, Niggemann B, Fang Q, Zaenker KS, Han R
The aim of the study was to investigate the antitumor and/or preventive effect of BC-4, an isomeric compound isolated from the plant Boswellia carteri Birdw. containing alpha- and beta-boswellic acid acetate in 1:1, MW 498.3. We used the MTT (3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide) assay to study the growth inhibition activity of BC-4. Tumor cells migration within a three-dimensional collagen matrix was recorded by time-lapse videomicroscopy and computer-assisted cell tracking. Topoisomerase II was isolated from mouse melanoma B16F10 cells and its activity was determined by its ability to cut plasmid pBR322 DNA. The secretion and activity of matrix metalloproteinases (MMPs) from human fibrosarcoma HT-1080 cells were determined by gelatin zymography. BC-4 was a cytostatic compound and could induce the differentiation of B16F10 mouse melanoma cells, blocked the cell population in G1 phase and inhibited topoisomerase II activity. The G1 phase population of B16F10 cells was increased from 57.4 to 87.7%, while S phase population was reduced from 33.3 to 5.9% after treatment with BC-4 at 25 microM concentration for 48 h. BC-4 also inhibited the migration activity of B16F10. BC-4 could induce apoptosis of HT-1080 cells, as proved by acridine orange fluorescence staining, Wright-Giemsa staining, electromicroscopy, DNA fragmentation and flow cytometry. BC-4 inhibited the secretion of MMPs from HT-1080 cells, too. In conclusion, if it turns out that BC-4 is a well tolerated substance, exhibiting no significant toxicity or side effects, being evaluated currently in China, BC-4 is a good candidate for the prevention of primary tumor, invasion and metastasis.
Cancer Detect Prev. 2003;27(1):67-75.
PMID: 12600419 [PubMed - indexed for MEDLINE]
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| 188. |
Cytostatic and apoptosis-inducing activity of boswellic acids toward malignant cell lines in vitro.
Hostanska K, Daum G, Saller R
Boswellic acids from frankincense were indentified as the active compounds which inhibit leukotriene biosynthesis, 5-lipoxygenase and exert antiproliferative activity toward a variety of malignant cells. Because of the relevance for the clinical application, we tested the ethanolic extract of Boswellia serrata gum resin containing a defined amount of boswellic acids for its cytotoxic, cytostatic and apoptotic activity on five leukemia (HL-60, K 562, U937, MOLT-4, THP-1) and two brain tumor (LN-18, LN-229) cell lines by WST-1 assay and flow cytometry. The Boswellia serrata extract induced dose-dependent antiproliferative effects on all human malignant cells tested with GI50 values (extract concentration producing 50% cell growth inhibition) between 57.0 and 124.1 micrograms/ml. In three haematological cell lines (K562, U937, MOLT-4) the effect of total extract expressed in GI50 was 2.8-, 3.3- and 2.3-times more potent (p < 0.05) than pure 3-O-acetyl-11-keto-beta-boswellic acid (AKBA). Morphological changes after 24-27 hours and the detection of apoptotic cells by AnnexinV-binding and/or by the detection of propidium iodide-labelled DNA with flow cytometry, confirmed the apoptotic cell death. The results of this study suggest the effectiveness of Boswellia serrata extract with defined content of boswellic acids.
Anticancer Res. 2002;22(5):2853-62.
PMID: 12530009 [PubMed - indexed for MEDLINE]
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| 189. |
Boswellic acids trigger apoptosis via a pathway dependent on caspase-8 activation but independent on Fas/Fas ligand interaction in colon cancer HT-29 cells.
Liu JJ, Nilsson A, Oredsson S, Badmaev V, Zhao WZ, Duan RD
Boswellic acids are the effective components of gum resin of Boswellia serrata, which has anti-inflammatory properties. Recent studies on brain tumors and leukemic cells indicate that boswellic acids may have antiproliferative and apoptotic effects with the mechanisms being not studied in detail. We studied their antiproliferative and apoptotic effects on colon cancer cells and the pathway leading to apoptosis. HT-29 cells were treated with beta-boswellic acid (BA), keto-beta-boswellic acid (K-BA) and acetyl-keto-beta-boswellic acid (AK-BA), respectively. Apoptosis was determined by flow cytometry, by cytoplasmic DNA-histone complex and the activity of caspase-3. The cleavage of poly-(ADP-ribose)-polymerase (PARP) and expression of Fas were examined by western blot. Specific caspase inhibitors, polyclonal Fas antibody, and antagonistic Fas antibody ZB4 were employed to elucidate apoptotic pathways. DNA synthesis and cell viability were examined. Both K-BA and AK-BA increased cytoplasmic DNA-histone complex dose-dependently and increased pre-G(1) peak in flow cytometer analysis, with the effects of AK-BA being stronger than K-BA. BA only increased the formation of DNA-histone complex at a high concentration. K-BA and AK-BA increased caspase-8, caspase-9 and caspase-3 activities accompanied by cleavage of PARP. The effects of AK-BA on formation of cytoplasmic DNA histone and on caspase-3 activation were 3.7- and 3.4-fold, respectively, more effective than those induced by camptothecin. The apoptosis induced by AK-BA was inhibited completely by caspase-3 or caspase-8 inhibitor and partially by caspase-9 inhibitor. ZB4 blocked exogenous Fas ligand-induced apoptosis, but had no effect on AK-BA-induced apoptosis. AK-BA had no significant effect on expression of Fas. Apart from apoptotic effect, these acids also inhibited [(3)H]thymidine incorporation and cell viability to different extent. In conclusion, boswellic acids, particularly AK-BA and K-BA have antiproliferative and apoptotic effects in human HT-29 cells. The apoptotic effect is mediated via a pathway dependent on caspase-8 activation but independent of Fas/FasL interaction.
Carcinogenesis. 2002 Dec;23(12):2087-93.
PMID: 12507932 [PubMed - indexed for MEDLINE]
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| 190. |
Keto- and acetyl-keto-boswellic acids inhibit proliferation and induce apoptosis in Hep G2 cells via a caspase-8 dependent pathway.
Liu JJ, Nilsson A, Oredsson S, Badmaev V, Duan RD
Boswellic acids are the compounds isolated from the gum resin of Boswellia serrata and have been used for the treatment of inflammatory diseases for many years in the countries of the east. Recently, a few studies showed that the acids may have anti-cancer effect on leukemia and brain tumours. We investigated the apoptotic and anti-proliferative effects of two types of boswellic acids, keto-beta-boswellic acid and acetyl-keto-beta-boswellic acid, on liver cancer Hep G2 cells. After treating the cells with the boswellic acids, cell proliferation, DNA synthesis, and apoptosis were analysed. The activities of caspase-3, -8 and -9 were assayed. To explore the apoptotic pathway, specific caspase inhibitors were employed. It was found that boswellic acids decreased cell viability and [3H]thymidine incorporation, checked the cells in the G1 phase, and increased percentage of sub-G1. Boswellic acids strongly induced apoptosis accompanied by activation of caspase-3, -8 and -9. The apoptosis was blocked completely by caspase-8 or caspase-3 inhibitor, but inhibited partly by caspase-9 inhibitor. However, these caspase inhibitors did not show any effect on the alternations of cell viability caused by boswellic acids. In conclusion, boswellic acids have anti-proliferation and anti-cancer effects on Hep G2 cells. The apoptotic effect is mediated by a pathway dependent on caspase-8 activation. The acids may be a promising drug for the chemoprevention of liver cancer.
Int J Mol Med. 2002 Oct;10(4):501-5.
PMID: 12239601 [PubMed - indexed for MEDLINE]
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| 191. |
[Experimental study on Jurkat cell apoptosis induced by Boswellia carterii Birdw extractive].
Liu X, Qi ZH
OBJECTIVE: To study the influence of Boswellia carterii Birdw(BCB) extractive of different concentrations on human Jurkat cell apoptosis at different time points.
METHODS: Agarose gel electrophoresis, transmission electron microscope(TEM) and flow cytometry(FCM) were used for observing DNA ladders, morphology of Jurkat cells and cell cycle, respectively.
RESULTS: BCB induced apoptosis of Jurkat cells and typical DNA ladders; TEM demonstrated the presence of apoptosis Jurkat cells, condensation of cytoplasm, numerous vaculoes in cytoplasm, compaction of the nuclear chromatin and formation of apoptosis dody. The sub-G1 peak was detected by cell cycle analysis. It revealed that G1 phage cells increased and S phage cells decreased.
CONCLUSION: The data indicate that BCB extractive induces time- and concentration-dependent apoptosis in Jurkat cell line.
Hunan Yi Ke Da Xue Xue Bao. 2000 Jun;25(3):241-4.
PMID: 12212153 [PubMed - indexed for MEDLINE]
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| 192. |
Cytotoxic action of acetyl-11-keto-beta-boswellic acid (AKBA) on meningioma cells.
Park YS, Lee JH, Bondar J, Harwalkar JA, Safayhi H, Golubic M
Acetyl-11-keto-beta-boswellic acid (AKBA) is a naturally occurring pentacyclic triterpene isolated from the gum resin exudate of the tree Boswellia serrata (frankincense). Because pentacyclic triterpenes have antiproliferative and cytotoxic effects against different tumor types, we investigated whether AKBA would act in a similar fashion on primary human meningioma cell cultures. Primary cell cultures were established from surgically removed meningioma specimens. The number of viable cells in the absence/presence of AKBA was determined by the non-radioactive cell proliferation assay. The activation status of the proliferative cell marker, extracellular signal-regulated kinase-1 and -2 (Erk-1 and Erk-2) was determined by immunoblotting with the antibody that recognizes the activated form of these proteins. Treatment of meningioma cells by AKBA revealed a potent cytotoxic activity with half-maximal inhibitory concentrations in the range of 2 - 8 microM. At low micromolar concentrations, AKBA rapidly and potently inhibited the phosphorylation of Erk-1/2 and impaired the motility of meningioma cells stimulated with platelet-derived growth factor BB. The cytotoxic action of AKBA on meningioma cells may be mediated, at least in part, by the inhibition of the Erk signal transduction pathway. Because of the central role the Erk pathway plays in signal transduction and tumorigenesis, further investigation into the potential clinical use for AKBA and related boswellic acids is warranted.
Planta Med. 2002 May;68(5):397-401.
PMID: 12058313 [PubMed - indexed for MEDLINE]
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| 193. |
[Experimental study on induction of apoptosis of leukemic cells by Boswellia carterii Birdw extractive].
Qi Z, Zhang G, Zhu W
The purpose of the study was to investigate the apoptosis of leukemic cells induced by Boswellia Carterii Birdw(BCB). The target leukemia cell line HL60 and bone marrow leukemic cells from 30 acute non-lymphocytic leukemic(ANLL) patients (3 M1 11 M2a 10 M3 1 M4a 5 M5b) were studied. Apoptosis was detected by morphological observation, DNA electrophoresis, percentage of DNA fragmentation test and flow cytometric cell cycle analysis. It is concluded that BCB can induce apoptosis in ANLL cells and HL60 cells.
Hunan Yi Ke Da Xue Xue Bao. 1999;24(1):23-5.
PMID: 11938731 [PubMed - indexed for MEDLINE]
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| 194. |
Anti-tumor and anti-carcinogenic activities of triterpenoid, beta-boswellic acid.
Huang MT, Badmaev V, Ding Y, Liu Y, Xie JG, Ho CT
Boswellin (BE), a methanol extract of the gum resin exudate of Boswellia serrata, contains naturally occurring triterpenoids, beta-boswellic acid and its structural related derivatives, has been used as a traditional medicine for the treatment of inflammatory and arthritic diseases. Topical application of BE to the backs of mice markedly inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced increases in skin inflammation, epidermal proliferation, the number of epidermal cell layers, and tumor promotion in 7,12-dimethylbenz[a]anthracene (DMBA)-initiated mice. Feeding 0.2% of BE in the diet to CF-1 mice for 10-24 weeks reduced the accumulation of parametrial fat pad weight under the abdomen, and inhibited azoxymethane (AOM)-induced formation of aberrant crypt foci (ACF) by 46%. Addition of pure beta-boswellic acid, 3-O-acetyl-beta-boswellic acid, 11-keto-beta-boswellic acid or 3-O-acetyl-11-keto-beta-boswellic acid to human leukemia HL-60 cell culture inhibited DNA synthesis in HL-60 cells in a dose-dependent manner with IC50 values ranging from 0.6 to 7.1 microM. These results indicate that beta-boswellic acid and its derivatives (the major constituents of Boswellin) have anti-carcinogenic, anti-tumor, and anti-hyperlipidemic activities.
Biofactors. 2000;13(1-4):225-30.
PMID: 11237186 [PubMed - indexed for MEDLINE]
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| 195. |
Boswellic acids inhibit glioma growth: a new treatment option?
Winking M, Sarikaya S, Rahmanian A, Jödicke A, Böker DK
Conventional malignant glioma therapy (surgery, radiation therapy and chemotherapy) does not yield satisfying results. The prognosis of the glioma patient depends more on the histological grading of the tumor and patient's age than on the therapy. Especially the adjuvant chemotherapy failed to date to influence survival time in glioma patients significantly. To improve results in malignant glioma therapy additional therapeutic regimes are necessary. In an earlier study we were able to show a significant reduction on perifocal edema by an extract from gum resin (EGR) accompanied with a clinical improvement in patients with malignant glioma. Also a decrease of urinary LTE4-excretion as a metabolite of leukotriene synthesis in brain tumors was observed. Furthermore we had found a proliferation inhibiting activity of the extract form EGR, the boswellic acids in cell cultures. The purpose of this experimental study was to elucidate the effects of the boswellic acids, which are constituents of an extract from gum resin on tumor growth in vivo. Female wistar rats weighing 200-250 g were treated with the drug 14 days after inoculation of C6 tumor cells into their right caudate nucleus and randomization into 4 groups. The treatment groups received different dosages and were compared to a control group without any additional treatment. Survival time of the rats in the highest dosage group (3 x 240 mg/kg body weight) was more than twice as long as in the control group (P < 0.05). In a second experiment the inhibition of tumor cell proliferation was examined. The C6 tumor cells were implanted into the caudate nucleus. Drug treatment was started immediately after implantation and stopped after 14 days. The animals were sacrificed and the brains were examined microscopically. Comparing low and high dosage of EGR treatment a significant difference in tumor volume was detected (P < 0.05). The proportion of apoptotic tumor cells in animals with high dose treatment was significantly larger than in the low dose (treatment) group (P < 0.05). These data demonstrate an influence of EGR in rat glioma growth and might represent a new therapeutic option on glioma treatment in man in future. Further experimental work on human gliomas is needed to definitively answer this question.
J Neurooncol. 2000;46(2):97-103.
PMID: 10894362 [PubMed - indexed for MEDLINE]
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| 196. |
Boswellic acids and malignant glioma: induction of apoptosis but no modulation of drug sensitivity.
Glaser T, Winter S, Groscurth P, Safayhi H, Sailer ER, Ammon HP, Schabet M, Weller M
Steroids are essential for the control of oedema in human malignant glioma patients but may interfere with the efficacy of chemotherapy. Boswellic acids are phytotherapeutic anti-inflammatory agents that may be alternative drugs to corticosteroids in the treatment of cerebral oedema. Here, we report that boswellic acids are cytotoxic to malignant glioma cells at low micromolar concentrations. In-situ DNA end labelling and electron microscopy reveal that boswellic acids induce apoptosis. Boswellic acid-induced apoptosis requires protein, but not RNA synthesis, and is neither associated with free radical formation nor blocked by free radical scavengers. The levels of BAX and BCL-2 proteins remain unaltered during boswellic acid-induced apoptosis. p21 expression is induced by boswellic acids via a p53-independent pathway. Ectopic expression of wild-type p53 also induces p21, and facilitates boswellic acid-induced apoptosis. However, targeted disruption of the p21 genes in colon carcinoma cells enhances rather than decreases boswellic acid toxicity. Ectopic expression of neither BCL-2 nor the caspase inhibitor, CRM-A, is protective. In contrast to steroids, subtoxic concentrations of boswellic acids do not interfere with cancer drug toxicity of glioma cells in acute cytotoxicity or clonogenic cell death assays. Also, in contrast to steroids, boswellic acids synergize with the cytotoxic cytokine, CD95 ligand, in inducing glioma cell apoptosis. This effect is probably mediated by inhibition of RNA synthesis and is not associated with changes of CD95 expression at the cell surface. Further studies in laboratory animals and in human patients are required to determine whether boswellic acids may be a useful adjunct to the medical management of human malignant glioma.
Br J Cancer. 1999 May;80(5-6):756-65.
PMID: 10360653 [PubMed - indexed for MEDLINE]
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| 197. |
Boswellic acid acetate induces differentiation and apoptosis in leukemia cell lines.
Jing Y, Nakajo S, Xia L, Nakaya K, Fang Q, Waxman S, Han R
Boswellic acid acetate (BC-4), a compound isolated from the herb Boswellia carterii Birdw., can induce differentiation and apoptosis of leukemia cells. Based on cell morphology and NBT reduction, BC-4 induced monocytic differentiation of myeloid leukemia HL-60, U937 and ML-1 cells at a dose under 12.5 microg/ml (24.2 microM). BC-4 was a potent inducer, with 90% of the cells showing morphologic changes and 80-90% of the cells showing NBT reduction. Specific and non-specific esterase were also increased by BC-4. Based on benzidine staining assay, BC-4 failed to induce erythroid leukemia DS-19 and K562 cells differentiation. In contrast to its selective differentiation effect, BC-4 strongly inhibited growth of all cell lines tested. The growth inhibition effect was dose- and time-dependent. In HL-60 cells, 20 microg/ml (38.8 microM) of BC-4 decreased viable cell number by 60% at 24 h, whereas at 3 days there was virtually no viable cells. Morphologic and DNA fragmentation analysis proved that BC-4 induced cell apoptosis. The dual apoptotic and differentiation effects of BC-4 suggest that it may be a powerful agent in the treatment of leukemia.
Leuk Res. 1999 Jan;23(1):43-50.
PMID: 9933134 [PubMed - indexed for MEDLINE]
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| 198. |
Acetyl-11-keto-beta-boswellic acid induces apoptosis in HL-60 and CCRF-CEM cells and inhibits topoisomerase I.
Hoernlein RF, Orlikowsky T, Zehrer C, Niethammer D, Sailer ER, Simmet T, Dannecker GE, Ammon HP
Antiproliferative action of different pentacyclic triterpenes has repeatedly been reported, and some lipoxygenase inhibitors have been shown to induce cell death in various cell systems. Acetyl-11-keto-beta-boswellic acid (AKBA) is a pentacyclic triterpene that inhibits 5-lipoxygenase in a selective, enzymedirected, nonredox, and noncompetitive manner. To investigate a possible effect of AKBA on leukemic cell growth, proliferation of HL-60 and CCRF-CEM cells was assayed in the presence of AKBA and a structural analog without effect on 5-lipoxygenase, amyrin. Cell counts and [3H]thymidine incorporation were significantly reduced in a dose-dependent manner in the presence of AKBA (IC50 = 30 microM) but not amyrin. An additive effect of AKBA with the crosslinking of the CD95 receptor was also observed. Flow cytometric analysis of propidium iodide-stained cells indicated that the cells underwent apoptosis. This was confirmed by flow cytometric detection of sub-G1 peaks in AKBA-treated cells and by DNA laddering. However, because HL-60 and CCRF-CEM do not express 5-lipoxygenase mRNA constitutively, a mechanism distinct from inhibition of 5-lipoxygenase must account for the effect of AKBA. In a DNA relaxation assay with phiX174RF DNA, AKBA inhibited topoisomerase I from calf thymus at concentrations of >/=10 microM. A semiquantitative cDNA polymerase chain reaction approach was used to estimate the relative level of expression of topoisomerases in both cell lines. The data suggest that induction of apoptosis in HL-60 and CCRF-CEM by AKBA may be due to inhibition of topoisomerase I in these cells.
J Pharmacol Exp Ther. 1999 Feb;288(2):613-9.
PMID: 9918566 [PubMed - indexed for MEDLINE]
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| 199. |
Inhibitory activity of boswellic acids from Boswellia serrata against human leukemia HL-60 cells in culture.
Shao Y, Ho CT, Chin CK, Badmaev V, Ma W, Huang MT
Four major triterpene acids including beta-boswellic acid (1), 3-O-acetyl-beta-boswellic acid (2), 11-keto-beta-boswellic acid (3), and 3-O-acetyl-11-keto-beta-boswellic acid (4) were isolated from the gum resin of Boswellia serrata and examined for their in vitro antitumor activity. They inhibited the synthesis of DNA, RNA and protein in human leukemia HL-60 cells in a dose dependent manner with IC50 values ranging from 0.6 to 7.1 microM. Among them, compound 4 induced the most pronounced inhibitory effects on DNA, RNA and protein synthesis with IC50 values of 0.6, 0.5, and 4.1 microM, respectively. The effect of 4 on DNA synthesis was found to be irreversible. Compound 4 significantly inhibited the cellular growth of HL-60 cells, but did not affect cell viability.
Planta Med. 1998 May;64(4):328-31.
PMID: 9619114 [PubMed - indexed for MEDLINE]
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| 200. |
Recent progress in the study of anticancer drugs originating from plants and traditional medicines in China.
Han R
Drugs of plant origin have received much attention due to their enormous potential for the prevention and treatment of cancer. Recent progress in the study of anticancer drugs originating from plants and traditional medicines in China is reviewed in this paper, with particular emphasis on taxol, daidzein, acetyl boswellic acid, curcumin and ginsenosid Rh2.
Chin Med Sci J. 1994 Mar;9(1):61-9.
PMID: 7916218 [PubMed - indexed for MEDLINE]
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| 201. |
Highlight on the studies of anticancer drugs derived from plants in China.
Han R
Recent progress on the study of anticancer drugs originating from plants in China is reviewed in this paper. Guided by the experience of traditional Chinese medicine, several new drugs have been found. Indirubin from Indigofera tinctoria is useful for the treatment of chronic myelocytic leukemia. Irisquinone from Iris latea pallasii and 10-hydroxy camptothecin from Camptotheca accuminata have exhibited definite activity on rodent tumors. Recent studies indicate that ginsenoside Rh2 is an inducer of cell differentiation in melanoma B-16 cells in vitro. Pharmacological studies have demonstrated that curcumin from Curcuma longa is an antimutagen as well as an antipromotor for cancer. Daidzein and acetyl boswellic acid have been shown to be effective inducers of cell differentiation in HL-60 cells. Guided by the chemotaxonomic principle of plants, harringtonine and homoharringtonine isolated from Cephalotaxus hainanesis have exhibited significant antileukemia activity and are widely used in clinics in China. Taxol from Taxus chinensis has been shown to be an important new anticancer drug with unique chemical structure and mechanism of action. The continuous search for new anticancer drugs from plants will be a fruitful frontier in cancer treatment and chemoprevention.
Stem Cells. 1994 Jan;12(1):53-63.
PMID: 8142920 [PubMed - indexed for MEDLINE]
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| 202. |
[Combination induction of cell differentiation of HL-60 cells by daidzein (S86019) and BC-4 or Ara-C].
Jing YK, Han R
Experiments demonstrated that the cell differentiation of HL-60 cells induced by low concentrations of daidzein (S86019), BC-4 (active principle of Boswellia carterii Birdw) and Ara-C was not impressive. However, when they were used in combination 80% of HL-60 cells exhibited NBT reduction and 82% of the cells showed phagocytosis after four days exposure to daidzein and BC-4. When HL-60 cells were exposed to daidzein and Ara-c, 70% of the cells exhibited NBT reduction and phagocytosis. Flow cytometry indicated that the majority of the cells were blocked at G1 phase under the induction of combination of daidzein with BC-4 or Ara-C.
Yao Xue Xue Bao. 1993;28(1):11-6.
PMID: 8328263 [PubMed - indexed for MEDLINE]
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| 203. |
Growth inhibition and differentiation of promyelocytic cells (HL-60) induced by BC-4, an active principle from Boswellia carterii Birdw.
Jing Y, Xia L, Han R
The induction of cell differentiation and growth inhibition of HL-60 cells by Bc-4, an active principle from Boswellia carterii, was studied in vitro and in vivo. The proliferation of HL-60 cells was found to be inhibited by Bc-4 at a concentration of 5-10 micrograms/ml. Under the action of Bc-4, the acid phosphatase and NBT reduction activities in HL-60 cells were increased, and phagocytosis of cells was also induced. All these activities were concentration dependent. The HL-60 cells were induced by Bc-4 to differentiate into more mature cells morphologically. The in vivo growth of HL-60 cells in mouse subrenal capsules (SRC) and in diffusion chambers inoculated into mice was inhibited by Bc-4 at a dose of 50 mg/kg. The morphology of HL-60 cells treated by Bc-4 in diffusion chambers exhibited characteristics of mature granulocytic cells.
Chin Med Sci J. 1992 Mar;7(1):12-5.
PMID: 1421355 [PubMed - indexed for MEDLINE]
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