Endometrial Kanserde Metformin Kullanımı

Endometrial kanser (EK) gelişmiş ülkelerde kadın genital sisteminin en sık görülen kanseridir. Önemli risk faktörleri olan obezite, Tip 2 Diabetes Mellitus ve insülin direncinin artışı ile birlikte tüm dünyada EK insidensi ve etkilenen genç hasta sayısı giderek artmaktadır. EK’de temel tedavi seçeneği olan cerrahi, fertiliteyi sonlandırması nedeni ile genç hastaları olumsuz olarak etkilemektedir. Ayrıca mevcut tedavi seçenekleri ileri evre ve rekürren EK’li hastalarda yetersiz kalmaktadır. Bu nedenle EK’li hastalar için yeni, etkili, cerrahi olmayan ve konservatif tedavi seçenekleri geliştirilmesi zorunlu görünmektedir. Bu açıdan antidiyabetik bir ilaç olan metformin EK tedavisi için güçlü bir aday olarak düşünülmektedir.

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  • 1. Xie W, Li T, Yang J et al. Metformin use and survival outcomes in endometrial cancer: a systematic review and meta-analysis. Oncotarget 2017;8(42):73079-73086.
  • 2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin 2016;66:7-30.
  • 3. Shafiee MN, Khan G, Ariffn R et al. Preventing endometrial cancer risk in polycystic ovarian syndrome (PCOS) women: could metformin help? Gynecol Oncol 2014;132(1):248-253.
  • 4. Fanning J. Treatment for early endometrial cancer. Cost-effctiveness analysis. J Reprod Med 1999;44(8):719-723.
  • 5. Dowling RJ, Goodwin PJ, Stambolic V. Understanding the benefit of metformin use in cancer treatment. BMC Med 2011;9:33.
  • 6. Gunter MJ, Hoover DR, Yu H et al. A prospective evaluation of insulin and insulin-like growth factor-I as risk factors for endometrial cancer. Cancer Epidemiol Biomarkers Prev 2008;17(4):921-929.
  • 7. Corzo C, Barrientos Santillan N, Westin SN et al. Updates on Conservative Management of Endometrial Cancer. J Minim Invasive Gynecol 2018;25(2):308-313.
  • 8. Shao R, Li X, Feng Y et al. Direct effcts of metformin in the endometrium: a hypothetical mechanism for the treatment of women with PCOS and endometrial carcinoma. J Exp Clin Cancer Res 2014;11: 33- 41.
  • 9. Chu D, Wu J, Wang K et al. Effct of metformin use on the risk and prognosis of endometrial cancer: a systematic review and meta-analysis. BMC Cancer 2018;18(1):438.
  • 10. Yeramian A, Moreno-Bueno G, Dolcet X et al. Endometrial carcinoma: molecular alterations involved in tumor development and progression. Oncogene 2013;32(4):403-413.
  • 11. Pollak M. Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer 2008;8(12):915-928.
  • 12. Tanabe K, Matsumoto M, Ikematsu S et al. Midkine and its clinical significance in endometrial carcinoma. Cancer Sci 2008;99(6):1125-1130.
  • 13. Wallbillich JJ, Josyula S, Saini U et al. High Glucose-Mediated STAT3 Activation in Endometrial Cancer Is Inhibited by Metformin: Therapeutic Implications for Endometrial Cancer. PLoS One 2017;12(1).
  • 14. 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(1):92- 98.
  • 15. Zhang J, Xu H, Zhou X et al. Role of metformin in inhibiting estrogen-induced proliferation and regulating ERα and ERβ expression in human endometrial cancer cells. Oncol Lett 2017;14(4):4949-4956.
  • 16. Bremer AA, Miller WL. The serine phosphorylation hypothesis of polycysticovary syndrome: a unifying mechanism for hyperandrogenemia and insulin resistance. Fertil Steril 2008;89(5):1039-1048.
  • 17. Li X, Guo YR, Lin JF et al. Combination of Diane-35 and Metformin to Treat Early Endometrial Carcinoma in PCOS Women with Insulin Resistance. J Cancer 2014;5(3):173-181.
  • 18. Clement NS, Oliver TR, Shiwani H et al. Metformin for endometrial hyperplasia: a Cochrane protocol. BMJ Open 2016 16;6(8):e013385.
  • 19. Pernicova I, Korbonits M. Metformin-mode of action and clinical implications for diabetes and cancer. Nat Rev Endocrinol 2014;10(3):143-156.
  • 20. Sivalingam VN, Myers J, Nicholas S et al. Metformin in reproductive health, pregnancy and gynaecological cancer: established and emerging indications. Hum Reprod Update 2014;20(6):853-868.
  • 21. Wang Y, Zhu Y, Zhang L et al. Insulin promotes proliferation, survival, and invasion in endometrial carcinoma by activating the MEK/ERK pathway. Cancer Lett 2012;322:223-231.
  • 22. Renehan AG, Tyson M, Egger M et al. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet 2008;371(9612):569-578.
  • 23. Chittenden BG, Fullerton G, Maheshwari A, Bhattacharya S. Polycystic ovary syndrome and the risk of gynaecological cancer: a systematic review. Reprod Biomed Online. 2009;19:398-405.
  • 24. Fearnley EJ, Marquart L, Spurdle AB et al. Polycystic ovary syndrome increases the risk of endometrial cancer in women aged less than 50 years: an Australian case–control study. Cancer Causes Control 2010;21:2303-2308.
  • 25. Xie Y, Wang YL, Yu L et al. Metformin promotes progesterone receptor expression via inhibition of mammalian target of rapamycin (mTOR) in endometrial cancer cells. J Steroid Biochem Mol Biol 2011;126:113-120
  • 26. Shao R, Li X, Billig H. Promising clinical practices of metformin in women with PCOS and early-stage endometrial cancer. BBA Clin 2014;2:7-9
  • 27. Zhao Y, Sun H, Feng M et al. Metformin is associated with reduced cell proliferation in human endometrial cancer by inbibiting PI3K/AKT/mTOR signaling. Gynecol Endocrinol 2018(5):428-432.
  • 28. Amant F, Moerman P, Neven P et al. Endometrial cancer. Lancet 2005;366:491-505.
  • 29. Di Cristofano A, Ellenson LH. Endometrial carcinoma. Ann Rev Pathol. 2007;2:57-85.
  • 30. Haoula Z, Salman M, Atiomo W. Evaluating the association between endometrial cancer and polycystic ovary syndrome. Hum Reprod. 2012;27:1327-1331.
  • 31. Del Barco S, Vazquez-Martin A, Cufi S et al. Metformin: multi-faceted protection against cancer. Oncotarget 2011;2:896-917.
  • 32. Dowling RJ, Niraula S, Stambolic V, Goodwin PJ. Metformin in cancer: translational challenges. J Mol Endocrinol 2012;48:R31-R43.
  • 33. Franciosi M, Lucisano G, Lapice E et al. Metformin therapy and risk of cancer in patients with type 2 diabetes: systematic review. PLoS One 2013;8:e71583.
  • 34. Nevadunsky NS, Van Arsdale A, Strickler HD et al. Metformin use and endometrial cancer survival. Gynecol Oncol 2014;132:236-240.
  • 35. Vallianou NG, Evangelopoulos A, Kazazis C. Metformin and cancer. Rev Diabet Stud 2013;10(4):228-235.
  • 36. Tan BK, Adya R, Chen J et al. Metformin treatment exerts antiinvasive and antimetastatic effcts in human endometrial carcinoma cells. J Clin Endocrinol Metab 011;96:808-816.
  • 37. Hanna RK, Zhou C, Malloy KM et al. Metformin potentiates the effcts of paclitaxel in endometrial cancer cells through inhibition of cell proliferation and modulation of the mTOR pathway. Gynecol Oncol 2012;125:458-469.
  • 38. Gu CJ, Cheng J, Zhang B et al. Protopanaxadiol and metformin synergistically inhibit estrogenmediated proliferation and anti-autophagy effcts in endometrial cancer cells. Am J Transl Res 2017;9(9):4071-4082.
  • 39. Kheirandish M, Mahboobi H, Yazdanparast M et al. Anti-cancer Effcts of Metformin: Recent Evidences for its Role in Prevention and Treatment of Cancer. Curr Drug Metab 2018;19(9):793-797.
  • 40. Liao H, Zhou Q, Gu Y et al. Luteinizing hormone facilitates angiogenesis in ovarian epithelial tumor cells and metformin inhibits the effct through the mTOR signaling pathway. Oncol Rep 2012;27:1873-1878.
  • 41. Arai M, Uchiba M, Komura H et al. Metformin, an antidiabetic agent, suppresses the production of tumor necrosis factor and tissue factor by inhibiting early growth response factor-1 expression in human monocytes in vitro. J Pharmacol Exp Ther 2010;334(1):206-213.
  • 42. Brown KA, Hunger NI, Docanto M, Simpson ER. Metformin inhibits aromatase expression in human breast adipose stromal cells via stimulation of AMP-activated protein kinase. Breast Cancer Res Treat 2010;123(2):591-596.