BCM-95® (CURCUGREEN®), 20 Mar 2015
Published on : Cancer Prev Res (Phila) . 2015 May;8(5):431-43. doi: 10.1158/1940-6207.CAPR-14-0354. Epub 2015 Feb 23.

Novel Evidence for Curcumin and Boswellic Acid-Induced Chemoprevention through Regulation of miR-34a and miR-27a in Colorectal Cancer

Shusuke Toden , Yoshinaga Okugawa , Constanze Buhrmann , Durgha Nattamai , Esperanza Anguiano , Nicole Baldwin , Mehdi Shakibaei , C Richard Boland , Ajay Goel

PMID: 25712055 PMCID: PMC4417447 DOI: 10.1158/1940-6207.CAPR-14-0354


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.

https://pubmed.ncbi.nlm.nih.gov/25712055/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4417447/


Keywords

  • bcm
  • BCM-95
  • bcm95
  • biocurcumax
  • boswellia serratta
  • clinical study
  • colorectal cancer
  • curcugreen
  • Curcumin
  • research
  • study

References

1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA: a cancer journal for clinicians. 2009;59:225–49. [PubMed[]
2. Willett WC. Diet and cancer: one view at the start of the millennium. Cancer epidemiology, biomarkers & prevention: a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2001;10:3–8. [PubMed[]
3. Buhrmann C, Mobasheri A, Matis U, Shakibaei M. Curcumin mediated suppression of nuclear factor-kappaB promotes chondrogenic differentiation of mesenchymal stem cells in a high-density co-culture microenvironment. Arthritis Res Ther. 2010;12:R127. [PMC free article] [PubMed[]
4. Rao CV, Simi B, Reddy BS. Inhibition by dietary curcumin of azoxymethane-induced ornithine decarboxylase, tyrosine protein kinase, arachidonic acid metabolism and aberrant crypt foci formation in the rat colon. Carcinogenesis. 1993;14:2219–25. [PubMed[]
5. Pereira MA, Grubbs CJ, Barnes LH, Li H, Olson GR, Eto I, et al. Effects of the phytochemicals, curcumin and quercetin, upon azoxymethane-induced colon cancer and 7,12-dimethylbenz[a]anthracene-induced mammary cancer in rats. Carcinogenesis. 1996;17:1305–11. [PubMed[]
6. Huang MT, Wang ZY, Georgiadis CA, Laskin JD, Conney AH. Inhibitory effects of curcumin on tumor initiation by benzo[a]pyrene and 7,12-dimethylbenz[a]anthracene. Carcinogenesis. 1992;13:2183–6. [PubMed[]
7. Rao CV, Rivenson A, Simi B, Reddy BS. Chemoprevention of colon carcinogenesis by dietary curcumin, a naturally occurring plant phenolic compound. Cancer research. 1995;55:259–66. [PubMed[]
8. Sethi S, Li Y, Sarkar FH. Regulating miRNA by natural agents as a new strategy for cancer treatment. Current drug targets. 2013;14:1167–74. [PMC free article] [PubMed[]
9. Lewis BP, Burge CB, Bartel DP. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell. 2005;120:15–20. [PubMed[]
10. Calin GA, Croce CM. MicroRNA signatures in human cancers. Nature reviews Cancer. 2006;6:857–66. [PubMed[]
11. Subramaniam D, Ponnurangam S, Ramamoorthy P, Standing D, Battafarano RJ, Anant S, et al. Curcumin induces cell death in esophageal cancer cells through modulating Notch signaling. PloS one. 2012;7:e30590. [PMC free article] [PubMed[]
12. Yang CH, Yue J, Sims M, Pfeffer LM. The curcumin analog EF24 targets NF-kappaB and miRNA-21, and has potent anticancer activity in vitro and in vivo. PloS one. 2013;8:e71130. [PMC free article] [PubMed[]
13. Ali S, Ahmad A, Banerjee S, Padhye S, Dominiak K, Schaffert JM, et al. Gemcitabine sensitivity can be induced in pancreatic cancer cells through modulation of miR-200 and miR-21 expression by curcumin or its analogue CDF. Cancer research. 2010;70:3606–17. [PMC free article] [PubMed[] Retracted
14. Kronski E, Fiori ME, Barbieri O, Astigiano S, Mirisola V, Killian PH, et al. miR181b is induced by the chemopreventive polyphenol curcumin and inhibits breast cancer metastasis via down-regulation of the inflammatory cytokines CXCL1 and -2. Molecular oncology. 2014;8:581–95. [PMC free article] [PubMed[]
15. Sreenivasan S, Thirumalai K, Danda R, Krishnakumar S. Effect of curcumin on miRNA expression in human Y79 retinoblastoma cells. Current eye research. 2012;37:421–8. [PubMed[]
16. Liu JJ, Nilsson A, Oredsson S, Badmaev V, Zhao WZ, Duan RD. 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. Carcinogenesis. 2002;23:2087–93. [PubMed[]
17. Takada Y, Ichikawa H, Badmaev V, Aggarwal BB. Acetyl-11-keto-beta-boswellic acid potentiates apoptosis, inhibits invasion, and abolishes osteoclastogenesis by suppressing NF-kappa B and NF-kappa B-regulated gene expression. J Immunol. 2006;176:3127–40. [PubMed[]
18. Glaser T, Winter S, Groscurth P, Safayhi H, Sailer ER, Ammon HP, et al. Boswellic acids and malignant glioma: induction of apoptosis but no modulation of drug sensitivity. British journal of cancer. 1999;80:756–65. [PMC free article] [PubMed[]
19. Lu M, Xia L, Hua H, Jing Y. Acetyl-keto-beta-boswellic acid induces apoptosis through a death receptor 5-mediated pathway in prostate cancer cells. Cancer research. 2008;68:1180–6. [PubMed[]
20. Yadav VR, Prasad S, Sung B, Gelovani JG, Guha S, Krishnan S, et al. Boswellic acid inhibits growth and metastasis of human colorectal cancer in orthotopic mouse model by downregulating inflammatory, proliferative, invasive and angiogenic biomarkers. International journal of cancer Journal international du cancer. 2012;130:2176–84. [PMC free article] [PubMed[]
21. Pang X, Yi Z, Zhang X, Sung B, Qu W, Lian X, et al. Acetyl-11-keto-beta-boswellic acid inhibits prostate tumor growth by suppressing vascular endothelial growth factor receptor 2-mediated angiogenesis. Cancer research. 2009;69:5893–900. [PMC free article] [PubMed[]
22. Park B, Sung B, Yadav VR, Cho SG, Liu M, Aggarwal BB. Acetyl-11-keto-beta-boswellic acid suppresses invasion of pancreatic cancer cells through the downregulation of CXCR4 chemokine receptor expression. International journal of cancer Journal international du cancer. 2011;129:23–33. [PMC free article] [PubMed[]
23. Takahashi M, Sung B, Shen Y, Hur K, Link A, Boland CR, et al. Boswellic acid exerts antitumor effects in colorectal cancer cells by modulating expression of the let-7 and miR-200 microRNA family. Carcinogenesis. 2012;33:2441–9. [PMC free article] [PubMed[]
24. Xu G, Ren G, Xu X, Yuan H, Wang Z, Kang L, et al. Combination of curcumin and green tea catechins prevents dimethylhydrazine-induced colon carcinogenesis. Food Chem Toxicol. 2010;48:390–5. [PubMed[]
25. Majumdar AP, Banerjee S, Nautiyal J, Patel BB, Patel V, Du J, et al. Curcumin synergizes with resveratrol to inhibit colon cancer. Nutrition and cancer. 2009;61:544–53. [PMC free article] [PubMed[]
26. Chou TC. Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer research. 2010;70:440–6. [PubMed[]
27. Link A, Shin SK, Nagasaka T, Balaguer F, Koi M, Jung B, et al. JC virus mediates invasion and migration in colorectal metastasis. PloS one. 2009;4:e8146. [PMC free article] [PubMed[]
28. Jascur T, Fotedar R, Greene S, Hotchkiss E, Boland CR. N-methyl-N′-nitro-N-nitrosoguanidine (MNNG) triggers MSH2 and Cdt2 protein-dependent degradation of the cell cycle and mismatch repair (MMR) inhibitor protein p21Waf1/Cip1. The Journal of biological chemistry. 2011;286:29531–9. [PMC free article] [PubMed[]
29. Shakibaei M, Mobasheri A, Lueders C, Busch F, Shayan P, Goel A. Curcumin enhances the effect of chemotherapy against colorectal cancer cells by inhibition of NF-kappaB and Src protein kinase signaling pathways. PloS one. 2013;8:e57218. [PMC free article] [PubMed[]
30. Shakibaei M. Inhibition of chondrogenesis by integrin antibody in vitro. Exp Cell Res. 1998;240:95–106. [PubMed[]
31. Yokoyama Y, Dhanabal M, Griffioen AW, Sukhatme VP, Ramakrishnan S. Synergy between angiostatin and endostatin: inhibition of ovarian cancer growth. Cancer research. 2000;60:2190–6. [PubMed[]
32. Oltvai ZN, Milliman CL, Korsmeyer SJ. Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell. 1993;74:609–19. [PubMed[]
33. Chen F, Hu SJ. Effect of microRNA-34a in cell cycle, differentiation, and apoptosis: a review. J Biochem Mol Toxicol. 2012;26:79–86. [PubMed[]
34. Pagliuca A, Valvo C, Fabrizi E, di Martino S, Biffoni M, Runci D, et al. Analysis of the combined action of miR-143 and miR-145 on oncogenic pathways in colorectal cancer cells reveals a coordinate program of gene repression. Oncogene. 2013;32:4806–13. [PubMed[]
35. Hermeking H. MicroRNAs in the p53 network: micromanagement of tumour suppression. Nature reviews Cancer. 2012;12:613–26. [PubMed[]
36. Noratto GD, Jutooru I, Safe S, Angel-Morales G, Mertens-Talcott SU. The drug resistance suppression induced by curcuminoids in colon cancer SW-480 cells is mediated by reactive oxygen species-induced disruption of the microRNA-27a-ZBTB10-Sp axis. Mol Nutr Food Res. 2013 [PubMed[]
37. Gandhy SU, Kim K, Larsen L, Rosengren RJ, Safe S. Curcumin and synthetic analogs induce reactive oxygen species and decreases specificity protein (Sp) transcription factors by targeting microRNAs. BMC cancer. 2012;12:564. [PMC free article] [PubMed[]
38. Jahid S, Sun J, Edwards RA, Dizon D, Panarelli NC, Milsom JW, et al. miR-23a promotes the transition from indolent to invasive colorectal cancer. Cancer Discov. 2012;2:540–53. [PMC free article] [PubMed[]
39. Cheng TS, Chen WC, Lin YY, Tsai CH, Liao CI, Shyu HY, et al. Curcumin-targeting pericellular serine protease matriptase role in suppression of prostate cancer cell invasion, tumor growth, and metastasis. Cancer prevention research. 2013;6:495–505. [PubMed[]
40. Jutooru I, Chadalapaka G, Lei P, Safe S. Inhibition of NFkappaB and pancreatic cancer cell and tumor growth by curcumin is dependent on specificity protein down-regulation. The Journal of biological chemistry. 2010;285:25332–44. [PMC free article] [PubMed[]
41. Liao X, Lochhead P, Nishihara R, Morikawa T, Kuchiba A, Yamauchi M, et al. Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival. The New England journal of medicine. 2012;367:1596–606. [PMC free article] [PubMed[]
42. Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990;61:759–67. [PubMed[]
43. Mertens-Talcott SU, Chintharlapalli S, Li X, Safe S. The oncogenic microRNA-27a targets genes that regulate specificity protein transcription factors and the G2-M checkpoint in MDA-MB-231 breast cancer cells. Cancer research. 2007;67:11001–11. [PubMed[]
44. Wang Z, Inuzuka H, Zhong J, Wan L, Fukushima H, Sarkar FH, et al. Tumor suppressor functions of FBW7 in cancer development and progression. FEBS Lett. 2012;586:1409–18. [PMC free article] [PubMed[]
45. Welcker M, Clurman BE. FBW7 ubiquitin ligase: a tumour suppressor at the crossroads of cell division, growth and differentiation. Nature reviews Cancer. 2008;8:83–93. [PubMed[]
46. Hollstein M, Sidransky D, Vogelstein B, Harris CC. p53 mutations in human cancers. Science. 1991;253:49–53. [PubMed[]
47. Levine AJ, Oren M. The first 30 years of p53: growing ever more complex. Nature reviews Cancer. 2009;9:749–58. [PMC free article] [PubMed[]
48. Choudhuri T, Pal S, Das T, Sa G. Curcumin selectively induces apoptosis in deregulated cyclin D1-expressed cells at G2 phase of cell cycle in a p53-dependent manner. The Journal of biological chemistry. 2005;280:20059–68. [PubMed[]
49. Cook NR, Lee IM, Zhang SM, Moorthy MV, Buring JE. Alternate-day, low-dose aspirin and cancer risk: long-term observational follow-up of a randomized trial. Ann Intern Med. 2013;159:77–85. [PMC free article] [PubMed[]
50. Anand P, Kunnumakkara AB, Newman RA, Aggarwal BB. Bioavailability of curcumin: problems and promises. Molecular pharmaceutics. 2007;4:807–18. [PubMed[]
51. Sterk V, Buchele B, Simmet T. Effect of food intake on the bioavailability of boswellic acids from a herbal preparation in healthy volunteers. Planta Med. 2004;70:1155–60. [PubMed[]
52. Prasad S, Tyagi AK, Aggarwal BB. Recent Developments in Delivery, Bioavailability, Absorption and Metabolism of Curcumin: the Golden Pigment from Golden Spice. Cancer Res Treat. 2014;46:2–18. [PMC free article] [PubMed[]
53. Tu SP, Jin H, Shi JD, Zhu LM, Suo Y, Lu G, et al. Curcumin induces the differentiation of myeloid-derived suppressor cells and inhibits their interaction with cancer cells and related tumor growth. Cancer prevention research. 2012;5:205–15. [PMC free article] [PubMed[]
54. Chandran B, Goel A. A randomized, pilot study to assess the efficacy and safety of curcumin in patients with active rheumatoid arthritis. Phytotherapy research: PTR. 2012;26:1719–25. [PubMed[]
55. Sanmukhani J, Satodia V, Trivedi J, Patel T, Tiwari D, Panchal B, et al. Efficacy and Safety of Curcumin in Major Depressive Disorder: A Randomized Controlled Trial. Phytotherapy research: PTR. 2013 [PubMed[]

Request More Information

We'll never share your email with anyone else.
We'll never share your email with anyone else.
We'll never share your company with anyone else.
We'll never share your country with anyone else.
We'll never share your contactNumber with anyone else.

We are always supporting our network of practitioners

Subscribe to our premium service for people like you who are passionate for science and want to know more about nature and its phenomena. Get detailed reports, methods and many more.

Increase your business growth potential with our patented extracts

Let’s collaborate to refine your ideas or built from scratch

Arjuna Natural

Arjuna Natural Ltd is India’s leading manufacturer and exporter of standardized botanical extracts for pharmaceutical and nutraceutical industries for more than two decades. Established in 1989, the company has grown...Read More

Get all the Updates about us!

For sales enquiries please email us at
sales@arjunanatural.com