Anticancer role of antidiabetic drug Metformin in ovarian cancer cells

Seema Patel, Neeta Singh, Lalit Kumar

Abstract


Purpose: Epithelial ovarian cancer is the most common ovarian cancer and has life threatening implications. Despite the progress in surgical and therapeutic strategies, resistance to chemotherapy is still a major concern. Chemotherapeutic agents cause cytotoxicity, primarily by the induction of apoptosis. The status of p53 is a key factor in determining the efficacy of apoptotic signaling. p53 is the most commonly mutated tumor suppressor gene in ovarian cancer. Metformin (an antidiabetic drug) has shown putative effects in many solid tumors. Hence we aimed to study the role of metformin in p53 mutated cancer cells.

Methods: SKOV3 and OAW42 ovarian cancer cell line were used. The cancer cells were treated with metformin. MTT, Flow cytometry and Western blotting were used to characterize the effects of the different treatments.

Results: Metformin treatment leads to cell cycle arrest in the G0/G1, S and G2/M phase of the cell cycle in SKOV3 and OAW42 respectively. Moreover, there was upregulation of Bax and downregulation of Bcl-2 protein and increased apoptosis in SKOV3 and OAW42 ovarian cancer cells.

Conclusion: These findings support the potential of metformin to be used as chemoadjuvant and reflects its ability to sensitize cancer cells to apoptosis independent of p53 status.


Keywords


Metformin, Ovarian Cancer, Apoptosis, p53

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References


Cristea M, Han E, Salmon L, et al. Practical considerations in ovarian cancer chemotherapy. Ther Adv Med Oncol. 2010;2:175-87.

Wilson TR, Johnston PG, Longley DB. Anti-apoptotic mechanisms of drug resistance in cancer. Curr Cancer Drug Targets. 2009;9:307-19.

Giménez-Bonafé P, Tortosa A, Pérez-Tomás R. Overcoming drug resistance by enhancing apoptosis of tumor cells. Curr Cancer Drug Targets. 2009;9:320-40.

Bayraktar S, Hernadez-Aya LF, Lei X, et al. Effect of Metformin on Survival Outcomes in Diabetic Patients with Triple Receptor–Negative Breast Cancer. Cancer. 2012;118:1202-11.

Demir U, Koehler A, Schneider R, Schweiger S, et al. Metformin anti-tumor effect via disruption of the MID1 translational regulator complex and AR downregulation in prostate cancer cells. BMC Cancer. 2014;14:52.

Gou S, Cui P, Li X et al. Low Concentrations of Metformin Selectively Inhibit CD133+ Cell Proliferation in Pancreatic Cancer and Have Anticancer Action. PLoS ONE. 2013;8.

Nangia-Makker P, Yu Y, Vasudevan A, et al. Metformin: A Potential Therapeutic Agent for Recurrent Colon Cancer. PLoS ONE. 2014;9.

Sato A, Sunayama J, Okada M, et al. Glioma-Initiating Cell Elimination by Metformin Activation of FOXO3 via AMPK. Stem Cells Transl Med. 2012;1:811-24.

Witters LA. The blooming of the French lilac. J Clin Invest. 2001;108:1105-7.

Cusi K, Consoli A, DeFronzo RA. Metabolic effects of metformin on glucose and lactate metabolism in noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab. 1996;81:4059-67.

Belfiore A, Frasca F. IGF and insulin receptor signaling in breast cancer. J Mammary Gland Biol Neoplasia. 2008;13:381-406.

Frasca F, Pandini G, Sciacca L, et al. The role of insulin receptors and IGF-I receptors in cancer and other diseases. Arch Physiol Biochem. 2008;114:23-37.

Mulligan AM, O'Malley FP, Ennis M et al. Insulin receptor is an independent predictor of a favorable outcome in early stage breast cancer. Breast Cancer Res Treat. 2007;106:39-47.

Goodwin PJ, Ligibel JA, Stambolic V. Metformin in breast cancer: time for action. J. Clin. Oncol. 2009;27:3271-3.

Ben Sahra I, Laurent K, Loubat A, et al. The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level. Oncogene. 2008;27:3576-86.

Rattan R, Giri S, Hartmann LC, Shridhar V. Metformin attenuates ovarian cancer cell growth in an AMP-kinase dispensable manner. J Cell Mol Med.2011;15:166-78.

Gotlieb WH, Saumet J, Beauchamp M-C et al. In vitro metformin anti-neoplastic activity in epithelial ovarian cancer. Gynecol Oncol. 2008;110:246-50.

Yasmeen A, Beauchamp M-C, Piura E et al. Induction of apoptosis by metformin in epithelial ovarian cancer: involvement of the Bcl-2 family proteins. Gynecol Oncol. 2011;121:492-8.

Schuijer M, Berns EMJJ. TP53 and ovarian cancer. Hum Mutat. 2003;21:285-91.

Kmet LM, Cook LS, Magliocco AM. A review of p53 expression and mutation in human benign, low malignant potential, and invasive epithelial ovarian tumors. Cancer. 2003;97:389-404.

Milner BJ. p53 mutation is a common genetic event in ovarian carcinoma Cancer Res. 1993;53:2128-32

Psyrri A, Kountourakis P, Yu Z, Papadimitriou C, et al. Analysis of p53 protein expression levels on ovarian cancer tissue microarray using automated quantitative analysis elucidates prognostic patient subsets. Ann Oncol. 2007;18:709–15.

Brachova P, Thiel KW, Leslie KK. The Consequence of Oncomorphic TP53 Mutations in Ovarian Cancer. Int J Mol Sci. 2013;14:19257-75.

Warenius HM, Jones M, Gorman T, et al. Combined RAF1 protein expression and p53 mutational status provides a strong predictor of cellular radiosensitivity. Br J Cancer. 2000;83:1084-95.

Hamroun D, Kato S, Ishioka C et al. The UMD TP53 database and website: update and revisions. Hum Mutat. 2006;27:14-20.

Sigal A, Rotter V. Oncogenic mutations of the p53 tumor suppressor: the demons of the guardian of the genome. Cancer Res. 2000;60:6788-93.

Patel S, Singh N, Kumar L. Evaluation of Effects of Metformin in Primary Ovarian Cancer Cells. Asian Pac J Cancer Prev. 2015;16:6973–79.

Sawant S, Shegokar R. Cancer research and therapy: Where are we today? Int J Cancer Ther Oncol 2014; 2(4):02048.

Mumtahana F, Tian X, Zhang T, Cui B. The efficacy and safety of Oxaliplatin-Vinorelbine as a second-line chemotherapy combination in patients with platinum-resistant pretreated epithelial ovarian cancer: A retrospective study. Int J Cancer Ther Oncol 2014; 2(4):020413.

Liu X, Zhang J, Li L, Yin F. Downregulation of transient receptor potential cation channel, subfamily C, member 1 (TRPC1) is associated with drug resistance and high histologic grade in ovarian cancer. Int J Cancer Ther Oncol 2015; 3(4):3409.

Brosh R, Rotter V. When mutants gain new powers: news from the mutant p53 field. Nat Rev Cancer. 2009;9:701-13.

Evans JMM, Donnelly LA, Emslie-Smith AM et al. Metformin and reduced risk of cancer in diabetic patients. BMJ. 2005;330:1304-5.

Bowker SL, Majumdar SR, Veugelers P et al. Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin. Diabetes Care. 2006;29:254-8.

Rocha GZ, Dias MM, Ropelle ER, et al. Metformin Amplifies Chemotherapy-Induced AMPK Activation and Antitumoral Growth. Clin Cancer Res. 2011;17:3993-4005.

Vermeulen K, Van Bockstaele DR, Berneman ZN. The cell cycle: a review of regulation, deregulation and therapeutic targets in cancer. Cell Prolif. 2003;36:131-49.

Kawabe T. G2 checkpoint abrogators as anticancer drugs. Mol Cancer Ther. 2004;3:513-9.

Takahashi A, Kimura F, Yamanaka A, et al. Metformin impairs growth of endometrial cancer cells via cell cycle arrest and concomitant autophagy and apoptosis. Cancer Cell Int. 2014;14:53.

Queiroz EAIF, Puukila S, Eichler R, et al. Metformin induces apoptosis and cell cycle arrest mediated by oxidative stress, AMPK and FOXO3a in MCF-7 breast cancer cells. PloS One. 2014;9:e98207

Takane H, Shikata E, Otsubo K et al. Polymorphism in human organic cation transporters and metformin action. Pharmacogenomics. 2008;9:415-22.

Berstein LM, Yue W, Wang J-P et al. Isolated and combined action of tamoxifen and metformin in wild-type, tamoxifen-resistant, and estrogen-deprived MCF-7 cells. Breast Cancer Res Treat. 2011;128:109-17.

Buzzai M, Jones RG, Amaravadi RK, et al. Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth. Cancer Res. 2007;67:6745-52.

Cantrell LA, Zhou C, Mendivil A et al. Metformin is a potent inhibitor of endometrial cancer cell proliferation--implications for a novel treatment strategy. Gynecol Oncol. 2010;116:92-8.

Cai X, Hu X, Tan X, et al. Metformin Induced AMPK Activation, G0/G1 Phase Cell Cycle Arrest and the Inhibition of Growth of Esophageal Squamous Cell Carcinomas In Vitro and In Vivo. PloS One. 2015;10:e0133349.




DOI: http://dx.doi.org/10.14319/ijcto.42.7

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