Repurposing metformin for the treatment of gastrointestinal cancer

Abstract

Diabetes mellitus type 2 and cancer share many risk factors. The pleiotropic insulin-dependent and insulin-independent effects of metformin might inhibit pathways that are frequently amplified in neoplastic tissue. Particularly, modulation of inflammation, metabolism, and cell cycle arrest are potential therapeutic cancer targets utilized by metformin to boost the anti-cancer effects of chemotherapy. Studies in vitro and in vivo models have demonstrated the potential of metformin as a chemo- and radiosensitizer, besides its chemopreventive and direct therapeutic activity in digestive system (DS) tumors. Hence, these aspects have been considered in many cancer clinical trials. Case-control and cohort studies and associated meta-analyses have evaluated DS cancer risk and metformin usage, especially in colorectal cancer, pancreatic cancer, and hepatocellular carcinoma. Most clinical studies have demonstrated the protective role of metformin in the risk for DS cancers and survival rates. On the other hand, the ability of metformin to enhance the actions of chemotherapy for gastric and biliary cancers is yet to be investigated. This article reviews the current findings on the anti-cancer mechanisms of metformin and its apparatus from pre-clinical and ongoing studies in DS malignancies.

Effect of Metformin on the Prognosis of Gastric Cancer Patients with Type 2 Diabetes Mellitus: A Meta-Analysis Based on Retrospective Cohort Studies

“…(4) Under hypoglycemic conditions, metformin strongly induces cell death by inhibiting the NADH dehydrogenase. Tis breaks the electron transport chain, and the anticancer efect may be greatly enhanced [47].…”

A direct bridge to metformin and matrix metalloproteinase relationship in prostate cancer model: oxidative stress

“…Especially considering that MMPs are inflammation markers, their effect on the cancerization process is inevitable 12 . Metformin, which is used as a type 2 diabetes treatment agent, has been known to slow down and sometimes stop carcinogenesis in recent years 13 . Prostate cancer seems to be the top cause of male death in the coming years.…”

Quo vadis PGRMC? Grand-Scale Biology in Human Health and Disease

“…Metformin inhibits the 5'-AMP-activated protein kinase (AMPK)/mTOR pathway and activates phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase (PTEN) to inhibit the PI3K/Akt pathway [447][448][449][450], which are important in the metabolic regulation and pluripotency maintenance of PSCs [451]. It is associated with reduced cancer risk and/or attenuation of cancer symptoms in a variety of cancers [452][453][454][455][456][457][458][459][460], as well as improvements in many inflammatory and age-related diseases, as well as lifespan and other hallmarks of aging [447][448][449][461][462][463].…”