On a global scale, a 60% increase in the burden of colorectal cancer (CRC) is expected by the year 2030 (Arnold et al., 2017). With rates of incidence continuing to rise, strategies for prevention and treatment are greatly needed to reduce both CRC onset and mortality and improve patient outcomes. A number of chemopreventive agents have gained attention for their ability to prevent carcinogenesis in colorectal cancer, among which include nonsteroidal anti-inflammatory drugs (NSAIDs) like Aspirin, natural compounds, Cyclooxygenase-2 inhibitors, and the antidiabetic drug metformin (Fajardo and Piazza, 2015). Notably the biguanide agent metformin, used in the treatment of type 2 diabetes mellitus, has demonstrated a reduction in risk of colon cancer and an anti-neoplastic effect, supported by clinical and epidemiological data (Bradley et al., 2018; Higurashi and Nakajima, 2018).

A synthetic biguanide derived from the guanidine extracts of Galega officinalis, or French lilac, metformin hydrochloride is today widely regarded as the drug of first-choice in the management of type 2 diabetes. The origin of the antidiabetic is linked to the use of G. officinalis, a folk remedy prescribed to alleviate conditions of polyuria and polydipsia, symptoms concomitant to diabetes (Witters, 2001; Bailey, 2017). The herb’s active ingredient, galegine (isoamylene guanidine), is a derivative of guanidine, a compound first reported by Watanabe (1918) to exert blood glucose-lowering effects in animals (Bailey, 2017; Watanabe, 1918). Subsequently, in 1922 metformin (dimethylbiguanide) was synthesized by Werner and Bell (1922). Existing primarily as a hydrophilic monoprotonated cation at physiologic pH, intestinal absorption is mediated largely by organic cation transporters (OCTs) (Gong et al., 2012) (Fig. 1).

Used as monotherapy or in combination with other antidiabetic drugs, metformin ameliorates the insulin resistance characteristic of type 2 diabetes and reduces endogenous glucose production through mechanisms believed to target largely the liver, namely by inhibiting gluconeogenesis and glycogenolysis (Scarpello and Howlett, 2008; Hundal et al., 2000). However, a number of studies have placed greater emphasis on the gut as a primary therapeutic target of metformin (Napolitano et al., 2014; Buse et al., 2016). Intravenously administered metformin has been shown to exhibit less efficacy than orally-administered drug, suggesting that metformin’s glucose-lowering effects may be largely mediated by presystemic mechanisms in the gut (Stepensky et al., 2002; Bonora et al., 1984). Buse et al. (2016) found that a novel formulation of delayed-release metformin (Met DR), which largely restricts metformin to the gut by targeting less absorptive distal bowel, proved more efficacious than formulations favoring systemic effect (Song, 2016; Buse et al., 2016). Thus, metformin’s intimate gut relationship and oral delivery make it quite favorable for targeting pathophysiology of the digestive tract, particularly colorectal cancer (Shen et al., 2018).

While metformin is generally known to act via both AMPK-dependent and independent mechanisms, its specific anti-neoplastic mechanisms in colorectal cancer remain a bit more elusive and not yet completely understood (Rena et al., 2017). This review aims to integrate and highlight more recent in-vitro and in-vivo discoveries that attempt to explain metformin’s anticancer properties via pharmacologic mechanism, specifically in colorectal cancer.