Metformin: A possible drug for treatment of endometrial cancer

Kosuke Tsuji, Iori Kisu, Kouji Banno, Megumi Yanokura, Arisa Ueki, Kenta Masuda, Yusuke Kobayashi, Wataru Yamagami, Hiroyuki Nomura, Nobuyuki Susumu, Daisuke Aoki

Department of Obstetrics and Gynecology, School of Medicine, Keio University, Tokyo, Japan.

DOI: 10.4236/ojog.2012.21001                

Abstract

Metformin is a widely used first-line drug for treatment of type 2 diabetes mellitus. In recent years, it has been reported that administration of metformin can reduce carcinogenic risk and inhibit proliferation of cancer cells including those from glioma and breast cancer. The underlying mechanism is thought to involve increased LKB-1 phosphorylation induced by metformin, followed by LKB-1 phosphorylation and activation of AMP-activated protein kinase (AMPK), which then inhibits the mammalian target of rapamycin (mTOR) pathway and results in inhibition of cell proliferation. In endometrial cancer, metformin causes cell cycle arrest in vitro, reduces hTERT mRNA, inhibits the mTOR pathway via AMPK, and is involved in inhibition of phosphorylation of S6 ribosomal protein (S6RP). Metformin promotes expression of progesterone receptor by an action opposite to that of insulin-like growth factor-2 (IGF-2) when used in combination with medroxyprogesterone acetate. This enhances the antitumor effect and this approach may be applicable in a clinical setting.

Keywords

Metformin; Endometrial Cancer; Type 2 Diabetes Mellitus; Mammalian Target of Rapamycin (mTOR); Progesterone Receptor (PR)

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	Nathan, D.M., Buse, J.B., Davidson, M.B., Heine, R.J., Holmann, R.R., Sherwin, R. and Zinman, B. (2006) Management of hyperglycemia in type 2 diabetes: A consensus algorithm for the initiation and adjustment of therapy: A consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care, 29, 1963-1972. doi:10.2337/dc06-9912
[2]	Nathan, D.M., Buse, J.B., Davidson, M.B., Ferrannini, E., Holman, R.R., Sherwin, R. and Zinman, B. (2009) Medical management of hyperglycemia in type 2 diabetes: A consensus algorithm for the initiation and adjustment of therapy: A consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care, 32, 193-203. doi:10.2337/dc08-9025
[3]	Bailey, C.J. (1992) Biguanides and NIDDM. Diabetes Care, 15,755-772. doi:10.2337/diacare.15.6.755
[4]	Bailey, C.J. and Turner, R.C. (1996) Metformin. The New England Journal of Medicine, 334, 574-579. doi:10.1056/NEJM199602293340906
[5]	Stumvoll, M., Nurjhan, N., Perriello, G., Dailey, G. and Gerich, J.E. (1995) Metabolic effects of metformin in non-insulin-dependent diabetes mellitus. The New England Journal of Medicine, 333, 550-554. doi:10.1056/NEJM199508313330903
[6]	(1995) United Kingdom Prospective Diabetes Study (UKPDS). 13: Relative efficacy of randomly allocated diet, sulphonylurea, insulin, or metformin in patients with newly diagnosed non-insulin dependent diabetes followed for three years. British Medical Journal, 310, 83-88. doi:10.1136/bmj.310.6972.83
[7]	Wu, M.S., Johnston, P., Sheu, W.H., Hollenbeck, C.B., Jeng, C.Y., Goldfine, I.D., Chen, Y.D. and Reaven, G.M. (1990) Effect of metformin on carbohydrate and lipoprotein metabolism in NIDDM patients. Diabetes Care, 13, 1-8. doi:10.2337/diacare.13.1.1
[8]	Stang, M., Wysowski, D.K. and Butler-Jones, D. (1999) Incidence of lactic acidosis in metformin users. Diabetes Care, 22, 925-927. doi:10.2337/diacare.22.6.925
[9]	Horlen, C., Malone, R., Bryant, B., Dennis, B., Carey, T., Pignone, M. and Rothman, R. (2002) Frequency of inappropriate metformin prescriptions. Journal of the American Medical Association, 287, 2504-2505. doi:10.1001/jama.287.19.2504-a
[10]	Calabrese, A.T., Coley, K.C., DaPos, S.V., Swanson, D. and Rao R.H. (2002) Evaluation of prescribing practices: Risk of lactic acidosis with metformin therapy. Archives of Internal Medicine, 162, 434-437. doi:10.1001/archinte.162.4.434
[11]	Masoudi, F.A., Wang, Y., Inzucchi, S.E., Setaro, J.F., Havranek, E.P., Foody, J.M. and Krumholz, H.M. (2003) Metformin and thiazolidinedione use in Medicare patients with heart failure. Journal of the American Medical Association, 290, 81-85. doi:10.1001/jama.290.1.81
[12]	Vasisht, K.P., Chen, S.C., Peng, Y. and Bakris, G.L. (2010) Limitations of metformin use in patients with kidney disease: Are they warranted? Diabetes, Obesity and Metabolism, 12, 1079-1083. doi:10.1111/j.1463-1326.2010.01295.x
[13]	Saydah, S.H., Loria, C.M., Eberhardt, M.S. and Brancati, F.L. (2003) Abnormal glucose tolerance and the risk of cancer death in the United States. American Journal of Epidemiology, 157, 1092-1100. doi:10.1093/aje/kwg100
[14]	Michels, K.B., Solomon, C.G., Hu, F.B., Rosner, B.A., Hankinson, S.E., Colditz, G.A. and Manson, J.E. (2003) Nurses’ Health Study. Type 2 diabetes and subsequent incidence of breast cancer in the Nurses’ Health Study. Diabetes Care, 26, 1752-1758. doi:10.2337/diacare.26.6.1752
[15]	Will, J.C., Galuska, D.A., Vinicor, F. and Calle, E.E. (1998) Colorectal cancer: Another complication of diabetes mellitus? American Journal of Epidemiology, 147, 816-825.
[16]	Everhart, J. and Wright, D. (1995) Diabetes mellitus as risk factor for pancreatic cancer: A meta-analysis. Journal of the American Medical Association, 273, 1605-1609. doi:10.1001/jama.1995.03520440059037
[17]	Gapstur, S.M., Gann, P.H., Colangelo, L.A., Barron-Simpson, R., Kopp, P., Dyer, A. and Liu, K. (2001) Postload plasma glucose concentration and 27-year prostate cancer mortality (United States). Cancer Causes Control, 12, 763-772. doi:10.1023/A:1011279907108
[18]	Evans, J.M., Donnelly, L.A., Emslie-Smith, A.M., Alessi, D.R. and Morris A.D. (2005) Metformin and reduced risk of cancer in diabetic patients. British Medical Journal, 330, 1304-1305. doi:10.1136/bmj.38415.708634.F7
[19]	Bowker, S.L., Yasui, Y., Veugelers, P. and Johnson, J.A. (2010) Glucose-lowering agents and cancer mortality rates in type 2 diabetes: Assessing effects of time-varying exposure. Diabetologia, 53, 1631-1637. doi:10.1007/s00125-010-1750-8
[20]	Libby, G., Donnelly, L.A., Donnan, P.T., Alessi, D.R. and Morris, A.D. (2009) Evans JMM. New users of metformin are at low risk of incident cancer: A cohort study among people with type 2 diabetes. Diabetes Care, 32, 1620-1625. doi:10.2337/dc08-2175
[21]	Moore, M.A., Park, C.B. and Tsuda, H. (1998) Implications of the hyperinsulinemia-diabetes-cancer link for preventive efforts. European Journal of Cancer Prevention, 7, 89-107.
[22]	Shaw, R.J., Lamia, K.A., Vasquez, D., Koo, S.H., Bardeesy, N., Depinho, R.A., Montminy, M. and Cantely, L.C. (2005) The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science, 310, 1642-1646. doi:10.1126/science.1120781
[23]	Isakovic, A., Harhaji, L., Stevanovic, D., Sumarac-Dumanovic, M., Starcevic, V., Micic, D. and Trajkovic, V. (2007) Dual antiglioma action of metformin: Cell cycle arrest and mitochondria-dependent apoptosis. Cellular and Molecular Life Sciences, 64, 1290-1302. doi:10.1007/s00018-007-7080-4
[24]	Baumann, P., Mandl-Weber, S., Emmerich, B., Stranka, C. and Schmidmaler, R. (2007) Inhibition of adenosine monophosphate-activated protein kinase induces apoptosis in multiple myeloma cells. Anticancer Drugs, 18, 405-410. doi:10.1097/CAD.0b013e32801416b6
[25]	Vucicevic, L., Misirkic, M., Janetovic, K., Harhaji-Trajkovic, L., Prica, M., Stevanovic, D., Isenovic, E., Sudar, E., Sumarac-Dumanovic, M., Micic, D. and Trajkovic, V. (2009) AMP-activated protein kinase-dependent and independent mechanisms underlying in vitro antiglioma action of compound C. Biochemical Pharmacology, 77, 1684-1693. doi:10.1016/j.bcp.2009.03.005
[26]	Buzzai, M., Jones, R.G., Amaravadi, R.K., Lum, J.J., DeBeradinis, R.J., Zhao, F., Viollet, B. and Thompson C.B. (2007) Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth. Cancer Research, 67, 6745-6752. doi:10.1158/0008-5472.CAN-06-4447
[27]	Wolf, I., Sedetzki, S., Catane, R., Karasik, A. and Kaufman, B. (2005) Diabetes mellitus and breast cancer. Lancet Oncology, 26,103-111. doi:10.1016/S1470-2045(05)01736-5
[28]	Liu, B., Fan, Z., Edgerton, S.M., Deng, X.S., Alimova, I.N., Lind, S.E. and Thor, A.D. (2009) Metformin induces unique biological and molecular responses in triple negative breast cancer cells. Cell Cycle, 8, 2031-2040. doi:10.4161/cc.8.13.8814
[29]	Alimova, I.N., Liu, B., Fan, Z., Edgerton, S.M., Dillion, T., Lind, S.E. and Thor, A.D. (2009) Metformin inhibits breast cancer cell growth, colony formation and induces cell cycle arrest in vitro. Cell Cycle, 8, 909-915. doi:10.4161/cc.8.6.7933
[30]	Sachdev, D., Singh, R., Fujita-Yamaguchi, Y. and Yee, D. (2006) Down-regulation of insulin receptor by antibodies against the type I insulin-like growth factor receptor: Implication for anti-insulin-like growth factor therapy in breast cancer. Cancer Research, 66, 2391-2402. doi:10.1158/0008-5472.CAN-05-3126
[31]	Zakikhani, M., Dowling, R., Fantus, G., Pollak, M. and Sonenberg, N. (2006) Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells. Cancer Research, 66, 10269-10273. doi:10.1158/0008-5472.CAN-06-1500
[32]	Rattan, R., Giri, S., Hartmann, L.C. and Shridhar, V. (2011) Metformin attenuates ovarian cancer cell growth in an AMP-kinase dispensable manner. Journal of Cellular and Molecular Medicine, 15, 166-178. doi:10.1111/j.1582-4934.2009.00954.x
[33]	Calle, E.E., Rodriguez, C., Walker-Thurmond, K. and Thun, M.J. (2003) Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. The New England Journal of Medicine, 348, 1625-1638. doi:10.1056/NEJMoa021423
[34]	Dronavalli, S. and Ehrmann, D.A. (2007) Pharmacologic therapy of polycystic ovary syndrome. Clinical Obstetrics and Gynecology, 50, 244-254. doi:10.1097/GRF.0b013e31802f35a0
[35]	Mutter, G.L., Lin, M.C., Fitzgerald, J.T., Kim, J.B., Baak, J.P., Lees, J.A., Weng, L.P. and Eng, C. (2000) Altered PTEN expression as a diagnostic marker for the earliest endometrial precancers. Journal of the National Cancer Institute, 92, 924-930. doi:10.1093/jnci/92.11.924
[36]	Lu, K.H., Wu, W., Dave, B., Slomovitz, B.M., Buruke, T.W., Munsell, M.F., Broaddus, R.R. and Walker, C.L. (2008) Loss of tuberous sclerosis complex-2 function and activation of mammalian target of rapamycin signaling in endometrial carcinoma. Clinical Cancer Research, 14, 2543-2450. doi:10.1158/1078-0432.CCR-07-0321
[37]	Cantrell, L.A., Zhou, C., Mendivil, A., Malloy, K.M., Gehrig, P.A. and Bae-Jump, V.L. (2010) Metformin is a potent inhibitor of endometrial cancer cell proliferation—Implications for a novel treatment strategy. Gynecologic Oncology, 116, 92-98. doi:10.1016/j.ygyno.2009.09.024
[38]	Zhou, C., Gehrig, P.A., Whang, Y.E. and Boggess, J.F. (2003) Rapamycin inhibits telomerase activity by decreasing the hTERT mRNA level in endometrial cancer cells. Molecular Cancer Therapeutics, 2, 789-795.
[39]	Xie, Y., Wang, Y.L., Yu, L., Hu, Q., Ji, L., Zhang, Y. and Liao, Q.P. (2011) Metformin promotes progesterone receptor expression via inhibition of mammalian target of rapamycin (mTOR) in endometrial cancer cells. Journal of Steroid Biochemistry and Molecular Biology, 126, 113-120. doi:10.1016/j.jsbmb.2010.12.006
[40]	Scheen, A.J. (1996) Clinical pharmacokinetics of metformin. Clinical Pharmacokinetics, 30, 359-371. doi:10.2165/00003088-199630050-00003
[41]	Wilcock, C. and Bailey, C.J. (1994) Accumulation of metformin by tissues of the normal and diabetic mouse. Xenobiotica, 24, 49-57. doi:10.3109/00498259409043220
[42]	Koepsell, H., Lips, K. and Volk, C. (2007) Polyspecific organic transporters: Structure, function, physiologic roles, and biopharmaceutical implications. Pharmaceutical Research, 24, 1227-1251. doi:10.1007/s11095-007-9254-z
[43]	Shu, Y., Sheardown, S., Brown, C., Owen, R.P., Zhang, S., Castro, R.A., Ianculescu, A.G., Yue, L., Lo, J.C., Burchard, E.G., Brett, C.M. and Glacomini, K.M. (2007) Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action. Journal of Clinical Investigation, 117, 1422-1431. doi:10.1172/JCI30558