BCM-95® (CURCUGREEN®), 23 Mar 2017
Published on : Carcinogenesis . 2017 Oct 1;38(10):1036-1046. doi: 10.1093/carcin/bgx065.
Kazuhiro Yoshida , Shusuke Toden , Preethi Ravindranathan , Haiyong Han , Ajay Goel
PMID: 29048549 PMCID: PMC5862331 DOI: 10.1093/carcin/bgx065
Kazuhiro Yoshida, Shusuke Toden, Preethi Ravindranathan, Haiyong Han and Ajay Goel
Abstract: Development of resistance to chemotherapeutic drugs is a major challenge in the care of patients with pancreatic ductal adenocarcinoma (PDAC). Acquired resistance to chemotherapeutic agents in PDAC has been linked to a subset of cancer cells termed “cancer stem cells” (CSCs). Therefore, an improved understanding of the molecular events underlying the development of pancreatic CSCs is required to identify new therapeutic targets to overcome chemoresistance. Accumulating evidence indicates that curcumin, a phenolic compound extracted from turmeric, can overcome de-novo chemoresistance and re-sensitize tumors to various chemotherapeutic agents. Curcumin was also found to prevent the formation of spheroids, a hallmark of cancer stem cells, and to down-regulate several self-renewal driving genes. In addition, we confirmed our in vitro findings in a xenograft mouse
model where curcumin inhibited gemcitabine-resistant tumor growth. Overall, this study indicates clinical relevance for combining curcumin with chemotherapy to overcome chemoresistance in PDAC.
Methods: Following 48 hour treatment with curcumin and/or gemcitabine, total cellular protein was extracted and western immunoblotting was performed
Results: The mechanism of gemcitabine resistance in CSCs is consistent with those in gemcitabine chemoresistant cell lines. Moreover, the study demonstrated that the characteristics of acquired gemcitabine-resistant cells resembled those of pancreatic cancer stem-like cells. Collectively, these results highlight the possibility of using curcumin as a sensitizer to chemotherapeutic drugs in chemoresistant PDACs in the clinical settings.
Conclusion: In summary, using a series of in vitro and in vivo experiments, we have demonstrated that curcumin inhibits PRC2-PVT1-c-Myc, which enhances sensitivity of cancer cells to chemotherapeutic agents by targeting CSCs. Our data is consistent with previous studies and highlights the potential of curcumin as a promising therapeutic agent in pancreatic cancer. Moreover, mechanistic investigation of natural compounds such as curcumin could result in the development of safer and more potent chemotherapeutic agents. Further investigations including clinical trials are needed to confirm the efficacy of this compound as an adjuvant to chemotherapeutic regimens.
© The Author 2017. Published by Oxford University Press. All rights reserved.
5. Avan A., et al. (2012)Molecular mechanisms involved in the synergistic interaction of the EZH2 inhibitor 3-deazaneplanocin A with gemcitabine in pancreatic cancer cells. Mol. Cancer Ther., 11, 1735–1746. [PMC free article] [PubMed] [Google Scholar]
8. Rajeshkumar N.V., et al. (2010)A combination of DR5 agonistic monoclonal antibody with gemcitabine targets pancreatic cancer stem cells and results in long-term disease control in human pancreatic cancer model. Mol. Cancer Ther., 9, 2582–2592. [PMC free article] [PubMed] [Google Scholar]
9. Sharma N., et al. (2015)PI3K/AKT/mTOR and sonic hedgehog pathways cooperate together to inhibit human pancreatic cancer stem cell characteristics and tumor growth. Oncotarget, 6, 32039–32060. [PMC free article] [PubMed] [Google Scholar]
10. Xia P., et al. (2015)PI3K/Akt/mTOR signaling pathway in cancer stem cells: from basic research to clinical application. Am. J. Cancer Res., 5, 1602–1609. [PMC free article] [PubMed] [Google Scholar]
15. Zhou Q., et al. (2016)Long noncoding RNA PVT1 modulates thyroid cancer cell proliferation by recruiting EZH2 and regulating thyroid-stimulating hormone receptor (TSHR). Tumour Biol., 37, 3105–13. [PubMed] [Google Scholar]
18. You L., et al. (2011)Genome-wide screen identifies PVT1 as a regulator of Gemcitabine sensitivity in human pancreatic cancer cells. Biochem. Biophys. Res. Commun., 407, 1–6. [PubMed] [Google Scholar]
23. Goel A., et al. (2010)Curcumin, the golden spice from Indian saffron, is a chemosensitizer and radiosensitizer for tumors and chemoprotector and radioprotector for normal organs. Nutr. Cancer, 62, 919–930. [PubMed] [Google Scholar]
25. Toden S., et al. (2015)Curcumin mediates chemosensitization to 5-fluorouracil through miRNA-induced suppression of epithelial-to-mesenchymal transition in chemoresistant colorectal cancer. Carcinogenesis, 36, 355–367. [PMC free article] [PubMed] [Google Scholar]
26. Fetoni A.R., et al. (2015)Molecular targets for anticancer redox chemotherapy and cisplatin-induced ototoxicity: the role of curcumin on pSTAT3 and Nrf-2 signalling. Br. J. Cancer, 113, 1434–1444. [PMC free article] [PubMed] [Google Scholar]
27. He M., et al. (2016)Re-purposing of curcumin as an anti-metastatic agent for the treatment of epithelial ovarian cancer: in vitro model using cancer stem cell enriched ovarian cancer spheroids. Oncotarget, 7, 86374–86387. [PMC free article] [PubMed] [Google Scholar]
28. Bao B., et al. (2012)Hypoxia-induced aggressiveness of pancreatic cancer cells is due to increased expression of VEGF, IL-6 and miR-21, which can be attenuated by CDF treatment. PLoS One, 7, e50165. [PMC free article] [PubMed] [Google Scholar]
29. Bao B., et al. (2012)Curcumin analogue CDF inhibits pancreatic tumor growth by switching on suppressor microRNAs and attenuating EZH2 expression. Cancer Res., 72, 335–345. [PMC free article] [PubMed] [Google Scholar]
30. Takahashi M., et al. (2012)Boswellic acid exerts antitumor effects in colorectal cancer cells by modulating expression of the let-7 and miR-200 microRNA family. Carcinogenesis, 33, 2441–2449. [PMC free article] [PubMed] [Google Scholar]
32. Jascur T., et al. (2011)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. J. Biol. Chem., 286, 29531–29539. [PMC free article] [PubMed] [Google Scholar]
33. de Sousa Cavalcante L., et al. (2014)Gemcitabine: metabolism and molecular mechanisms of action, sensitivity and chemoresistance in pancreatic cancer. Eur. J. Pharmacol., 741, 8–16. [PubMed] [Google Scholar]
34. Sahu R.P., et al. (2009)Activation of ATM/Chk1 by curcumin causes cell cycle arrest and apoptosis in human pancreatic cancer cells. Br. J. Cancer, 100, 1425–1433. [PMC free article] [PubMed] [Google Scholar]
35. Saiki Y., et al. (2009)Comprehensive analysis of the clinical significance of inducing pluripotent stemness-related gene expression in colorectal cancer cells. Ann. Surg. Oncol., 16, 2638–2644. [PubMed] [Google Scholar]
36. Porro A., et al. (2010)Direct and coordinate regulation of ATP-binding cassette transporter genes by Myc factors generates specific transcription signatures that significantly affect the chemoresistance phenotype of cancer cells. J. Biol. Chem., 285, 19532–19543. [PMC free article] [PubMed] [Google Scholar]
37. Liao D.J., et al. (2007)Perspectives on c-Myc, Cyclin D1, and their interaction in cancer formation, progression, and response to chemotherapy. Crit. Rev. Oncog., 13, 93–158. [PubMed] [Google Scholar]
40. Hou Y.C., et al. (2014)Coexpression of CD44-positive/CD133-positive cancer stem cells and CD204-positive tumor-associated macrophages is a predictor of survival in pancreatic ductal adenocarcinoma. Cancer, 120, 2766–2777. [PMC free article] [PubMed] [Google Scholar]
41. Mizukami T., et al. (2014)Immunohistochemical analysis of cancer stem cell markers in pancreatic adenocarcinoma patients after neoadjuvant chemoradiotherapy. BMC Cancer, 14, 687. [PMC free article] [PubMed] [Google Scholar]
42. Ali S., et al. (2010)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 Res., 70, 3606–3617. [PMC free article] [PubMed] [Google Scholar] Retracted
43. Kunnumakkara A.B., et al. (2007)Curcumin potentiates antitumor activity of gemcitabine in an orthotopic model of pancreatic cancer through suppression of proliferation, angiogenesis, and inhibition of nuclear factor-kappaB-regulated gene products. Cancer Res., 67, 3853–3861. [PubMed] [Google Scholar]
44. Hemming S., et al. (2016)Identification of novel EZH2 targets regulating osteogenic differentiation in mesenchymal stem cells. Stem Cells Dev., 25, 909–921. [PMC free article] [PubMed] [Google Scholar]
45. Ougolkov A.V., et al. (2008)Regulation of pancreatic tumor cell proliferation and chemoresistance by the histone methyltransferase enhancer of zeste homologue 2. Clin. Cancer Res., 14, 6790–6796. [PMC free article] [PubMed] [Google Scholar]
48. Zhuang C., et al. (2015)Tetracycline-inducible shRNA targeting long non-coding RNA PVT1 inhibits cell growth and induces apoptosis in bladder cancer cells. Oncotarget, 6, 41194–41203. [PMC free article] [PubMed] [Google Scholar]
50. Takahashi Y., et al. (2014)Amplification of PVT-1 is involved in poor prognosis via apoptosis inhibition in colorectal cancers. Br. J. Cancer, 110, 164–171. [PMC free article] [PubMed] [Google Scholar]
51. Zhang X.W., et al. (2015)Overexpression of long non-coding RNA PVT1 in gastric cancer cells promotes the development of multidrug resistance. Biochem. Biophys. Res. Commun., 462, 227–232. [PubMed] [Google Scholar]
52. Liu E., et al. (2015)Carboplatin-docetaxel-induced activity against ovarian cancer is dependent on up-regulated lncRNA PVT1. Int. J. Clin. Exp. Pathol., 8, 3803–3810. [PMC free article] [PubMed] [Google Scholar]