Could there be a role for the antidiabetic drug metformin in oncological treatment?

Diabetes and tumour diseases are serious health problems in the elderly population. Several studies have suggested that patients with diabetes are at significantly higher risk of cancer. On the other hand, epidemiologic evidence suggests that some drugs used to treat hyperglycemia are associated with reduced risk of cancer. Metformin, the drug applied in type 2 diabetes, has been shown to reduce incidence and mortality due to malignant tumours in various localities. A hypothesis is presented which seeks to explain the anticancer effects of metformin. Empirical data from the scientific literature is used to support the hypothesis that metformin restricts the growth of human cancer stem cells (CSCs). The LKB1/AMPK (liver kinase B1/AMP activated protein kinase) mechanism of the antineoplastic action is pleiotropic, involving the activation of the LKB1/AMP pathway, which inhibits mTOR signalling, inhibits STAT-3 phosphorylation, arrests cell cycle at the G1 phase, inhibits cyclin D1 activity, reduces insulin levels, as well as IGF-1, TNFα, and IL-6 levels which reduce proliferation leading to apoptosis of neoplastic cells. In various tumours, including gynaecological cancers, metformin eliminates cancer stem cells (CSCs). Repositioning metformin as a possible antineoplastic option seems promising. The present authors suggest here that metformin could be a valuable tool for clinicians to help reduce cancer risk in elderly adults with diabetes.

Metformin; Ovarian cancer; Endometrial cancer; Cancer stem cells; Diabetes.

[1] Baley C.J., Day C.: “Metformin: its botanical background”. Pract. Diab. Int., 2014, 21, 115.

[2] Rosta A.: “Diabetes and cancer risk: oncologic considerations”. Orv. Hetil., 2011, 152, 1144.

[3] Arnold M., Pandeya N., Byrnes G., Renehan P.A.G., Stevens G.A., Ezzati PM. et al.: “Global burden of cancer attributable to high bodymass index in 2012: a population-based study”. Lancet Oncol., 2015, 16, 36.

[4] Drake I., Gullberg B., Sonestedt E., Stocks T., Bjartell A., Wirfalt E. et al.: “Type 2 diabetes, adiposity and cancer morbidity and mortality risk taking into account competing risk of noncancer deaths in a prospective cohort setting”. Int. J. Cancer, 2017, 141, 1170.

[5] Evans J.M., Donnelly L.A., Emslie-Smith A.M., Alessi D.R., Morris A.D.: “Metformin and reduced risk of cancer in diabetic patients”. BMJ, 2005, 330, 1304.

[6] Libby G., Donnelly L.A., Donnan P.T., Alessi D.R., Morris A.D., Evans J.M.: “New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes”. Diabetes Care, 2009, 32, 1620.

[7] Daugan M., Dufaÿ Wojcicki A., d’Hayer B., Boudy V.: “Metformin: An anti-diabetic drug to fight cancer”. Pharmacol. Res., 2016, 113, 675.

[8] Zhou X.L., Xue W.H., Ding X.F., Li L.F., Dou M.M., Zhang W.J., et al.: “Association between metformin and the risk of gastric cancer in patients with type 2 diabetes mellitus: a meta-analysis of cohort studies”. Oncotarget, 2017, 8, 55622.

[9] Decensi A., Puntoni M., Goodwin P., Cazzaniga M., Gennari A., Bonanni B., et al.: “Metformin and cancer risk in diabetic patients: a systematic review and meta-analysis”. Cancer Prev. Res. (Phila.), 2010, 3, 1451.

[10] Gandini S., Puntoni M., Heckman-Stoddard BM., Dunn BK., Ford L., DeCensi A. et al.: “Metformin and cancer risk and mortality: a systematic review and meta-analysis taking into account biases and confounders”. Cancer Prev. Res. (Phila.), 2014, 7, 867.

[11] Zhang P., Li H., Tan X., Chen L., Wang S.: “Association of metformin use with cancer incidence and mortality: a meta-analysis”. Cancer Epidemiol., 2013, 37, 207.

[12] Bowker S.L., Majumdar S.R., Veugelers P., Johnson J.A.: “Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin”. Diabetes Care, 2006, 29, 254.

[13] Landman G.W., Kleefstra N., van Hateren K.J., Groenier K.H., Gans R.O., Bilo H.J.: “Metformin associated with lower cancer mortality in type 2 diabetes: ZODIAC-16”. Diabetes Care, 2010, 33, 322.

[14] Gadduci A., Biglia N., Tana R., Cosio S., Gallo M.: “Metformin use and gynecological cancers: A novel treatment option emerging from drug repositioning”. Crit. Rev. Oncol. Hematol., 2016, 105, 73.

[15] Del Barco S., Vazquez-Martin A., Cufí S., Oliveras-Ferraros C., Bosch-Barrera J., Joven J., et al.: “Metformin: multi-faceted protection against cancer”. Oncotarget, 2011, 2, 896.

[16] Dowling R.J., Goodwin P.J., Stambolic V.: “Understanding the benefit of metformin use in cancer treatment”. BMC Med., 2011, 9, 33.

[17] Vallianou N.G., Evangelopoulos A., Kazazis C.: “Metformin and cancer”. Rev. Diabet. Stud., 2013, 10, 228.

[18] Feng F., Zhang J., Fan X., Yuan F., Jiang Y., Lu R., et al.: “Downregulation of Rab27A contributes to metformin-induced suppression of breast cancer stem cells”. Oncol. Lett., 2017, 14, 2947.

[19] Vazquez-Martin A., Oliveras-Ferraros C., Menendez J.A.: “The antidiabetic drug metformin suppresses HER2 (erbB-2) oncoprotein overexpression via inhibition of the mTOR effector p70S6K1 in human breast carcinoma cells”. Cell Cycle, 2009, 8, 88.

[20] Bao B., Azmi AS., Ali S., Zaiem F., Sarkar F.H.: “Metformin may function as anti-cancer agent via targeting cancer stem cells: the potential biological significance of tumor-associated miRNAs in breast and pancreatic cancers”. Ann. Transl. Med., 2014, 2, 59.

[21] Shank J.J., Yang K., Ghannam J., Cabrera L., Johnston C.J., Reynolds R.K., et al.: “Metformin targets ovarian cancer stem cells in vitro and in vivo”. Gynecol. Oncol., 2012, 127, 390.

[22] Hirsch H.A., Iliopoulos D., Tsichlis P.N., Struhl K.: “Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission”. Cancer Res., 2009, 69, 7507.

[23] Zhang R., Zhang P., Wang H., Hou D., Li W., Xiao G., et al.: “Inhibitory effects of metformin at low concentration on epithelial-mesenchymal transition of CD44(+)CD117(+) ovarian cancer stem cells”. Stem Cell Res. Ther., 2015, 6, 262.

[24] Dilokthornsakul P., Chaiyakunapruk N., Termrungruaglert W., Pratoomsoot C., Saokaew S., Sruamsiri R.: “The effects of metformin on ovarian cancer. A systematic review”. Int. J. Gynecol. Cancer, 2013, 23, 1544.

[25] Meireles C.G., Pereira S.A., Valadares L.P., Rêgo D.F., Simeoni L.A., Guerra E.N.S., et al.: “Effects of metformin on endometrial cancer: Systematic review and metaanalysis”. Gynecol. Oncol., 2017, 147, 167.

[26] de Barros Machado A., Dos Reis V., Weber S., Jauckus J., Brum I.S., von Eye Corleta H., et al.: “Proliferation and metastatic potential of endometrial cancer cells in response to metformin treatment in a high versus normal glucose environment”. Oncol. Lett., 2016, 12, 3626.

[27] Irie H., Banno K., Yanokura M., Iida M., Adachi M., Nakamura K., et al.: “Metformin: A candidate for the treatment of gynecological tumors based on drug repositioning”. Oncol. Lett., 2016, 11, 1287.