Metformin as Adjuvant Therapy in Ovarian and Endometrial Cancers

Abstract

Obesity has been linked with increased risk for and worse outcomes from cancer, including gynecologic cancers. Metformin (1,1-dimethylbiguanide) is a biguanide anti-hyperglycemic widely used for the treatment of type 2 diabetes. Epidemiologic studies suggest metformin both lowers cancer risk and improves cancer outcomes in diabetic patients when compared to those treated with other anti-diabetic medications. This epidemiologic evidence prompted pre-clinical investigation of the effects of metformin in cancer. In vitro and in vivo data find that metformin possesses anti-cancer effects through both indirect and direct effects on tumor growth. Indirect effects are likely due to inhibition of hepatic gluconeogenesis, resulting in reduced circulating glucose and insulin levels, which may decrease growth factor-stimulated tumor growth. Metformin may directly affect tumor growth through inhibition of mitochondrial complex 1 and activation of adenosine monophosphate-activated protein kinase (AMPK), resulting in the regulation of multiple downstream signaling pathways that control cell proliferation and metabolism, including inhibition of the mammalian target of rapamycin (mTOR) pathway as well as decreased fatty acid and lipid sythesis.