Metformin: A Possible Option in Cancer Chemotherapy

Abstract

Metformin has been used for a long time as an antidiabetic medication for type 2 diabetes. It is used either as a monotherapy or in combination with other antidiabetic medications. The drug came into prominence in diabetes and other conditions with cardiovascular risk after the landmark study of 1995 by the United Kingdom Prospective Diabetes Study which emphasized its importance. However, the drug has been used in experimental trials in various aspects of medicine and pharmacology such as in reproductive medicine, cancer chemotherapy, metabolic diseases, and neurodegenerative diseases. It has been in use in the treatment of polycystic ovarian disease and obesity and is being considered in type 1 diabetes. This study seeks to evaluate the relevance of metformin in cancer management. Different mechanisms have been proposed for its antitumor action which involves the following: (a) the activation of adenosine monophosphate kinase, (b) modulation of adenosine A1 receptor (ADORA), (c) reduction in insulin/insulin growth factors, and (d) the role of metformin in the inhibition of endogenous reactive oxygen species (ROS); and its resultant damage to deoxyribonucleic acid (DNA) molecule is another paramount antitumor mechanism.

Hypoxia-induced therapy resistance: Available hypoxia-targeting strategies and current advances in head and neck cancer

“…Unfortunately, BEZ-235 (Dactolisib) showed high toxicity levels in preclinical studies and the completed clinical trials so far have not obtained any benefits [65] . On the contrary, metformin (Glucophage), which indirectly inhibits mTORC1 through activation of the adenosine monophosphate protein kinase (AMPK) [66] , has obtained promising results and is currently ongoing several clinical trials in breast cancer (NCT01101438), endometrial cancer (NCT01697566), colorectal cancer (NCT02614339), prostate cancer (NCT01864096) and oral cancer (NCT03685409 and NCT02581137). Differently to metformin, rapamycin (Rapamune) is an allosteric inhibitor that directly inhibits mTOR by binding to its FKBP-rapamycin-binding (FRB) domain and so far, encouraging results have been obtained in preclinical and clinical studies in prostate cancer patients [ 44 , 67 ].…”

Perspectives on Hypoxia Signaling in Tumor Stroma

“…For example, sirolimus, an mTOR inhibitor has shown encouraging results in preclinical and clinical studies in prostate cancer [ 164 , 165 ]. Furthermore, metformin indirectly inhibits mTORC1 through activation of the AMPK pathway and has also demonstrated promising results [ 166 ]. Furthermore, in preclinical models, metformin has been linked to increased T cell activation, working synergistically with checkpoint blockade [ 167 ].…”

Metformin and Androgen Receptor-Axis-Targeted (ARAT) Agents Induce Two PARP-1-Dependent Cell Death Pathways in Androgen-Sensitive Human Prostate Cancer Cells

“…The finding that patients with diabetes taking metformin, but not other anti-diabetic drugs, have a decreased risk of dying from PC [11,12] led to extensive studies on the anti-tumor effects of metformin in PC. Pre-clinical studies demonstrate that metformin can down-regulate AR by disrupting the protein midline-1 (MID1) complex, which otherwise increases AR via enhanced translation [13].…”