Metformin in colorectal cancer: molecular mechanism, preclinical and clinical aspects

Abstract

Growing evidence showed the increased prevalence of cancer incidents, particularly colorectal cancer, among type 2 diabetic mellitus patients. Antidiabetic medications such as, insulin, sulfonylureas, dipeptyl peptidase (DPP) 4 inhibitors and glucose-dependent insulinotropic peptide (GLP-1) analogues increased the additional risk of different cancers to diabetic patients. Conversely, metformin has drawn attention among physicians and researchers since its use as antidiabetic drug exhibited beneficial effect in the prevention and treatment of cancer in diabetic patients as well as an independent anticancer drug. This review aims to provide the comprehensive information on the use of metformin at preclinical and clinical stages among colorectal cancer patients. We highlight the efficacy of metformin as an anti-proliferative, chemopreventive, apoptosis inducing agent, adjuvant, and radio-chemosensitizer in various colorectal cancer models. This multifarious effects of metformin is largely attributed to its capability in modulating upstream and downstream molecular targets involved in apoptosis, autophagy, cell cycle, oxidative stress, inflammation, metabolic homeostasis, and epigenetic regulation. Moreover, the review highlights metformin intake and colorectal cancer risk based on different clinical and epidemiologic results from different gender and specific population background among diabetic and non-diabetic patients. The improved understanding of metformin as a potential chemotherapeutic drug or as neo-adjuvant will provide better information for it to be used globally as an affordable, well-tolerated, and effective anticancer agent for colorectal cancer.

Keywords: Anticancer; Cancer; Chemopreventive; Colorectal cancer; Metformin; Type 2 diabetes mellitus.

Fig. 1

The anticancer molecular mechanisms mediated by metformin through the modulation of AMPK and cellular energy homeostasis. Metformin mainly modulates AMPK activation through LKB1 which activates and/or inactivates various downstream signalling targets such as mTOR, PTEN/PI3K-Akt, MAPKs, transcription factors (NF-κB, FOXO) and p53. The activation of these signalling pathways induce oxidative stress, apoptosis and cell cycle arrestment that inhibited formation of ACF and tumorigenesis in the colon cancer cell while suppressing cellular inflammation that is responsible to promote cell proliferation. The signalling activation or inhibition mediated by metformin is denoted by the red arrows and inhibition arrows, reversing the tumorigenesis mechanism indicated by the blue arrows