The biguanides metformin and phenformin are antidiabetic drugs with documented antitumor properties in colorectal cancer (CRC). Despite intensive research, the mechanism of action of biguanides in cancer is still unclear. The most accepted model links their effect to inhibition of mitochondrial complex I, thereby causing energy stress with activation of AMPK and mTOR inhibition. However, this model has been questioned since complex I inhibition requires millimolar concentrations of biguanides but these values cannot be reached in patients and animal models, where the maximum tolerated doses are within the micromolar range. Recent studies in diabetic patients have shown that the weight- and glucose-lowering properties of biguanides are related to their ability to increase secretion of GDF15, a stress induced cytokine, independently of complex I. However, whether GDF15 may also mediate the therapeutic effect of biguanides in cancer is currently unknown.
Our working hypothesis is that biguanides inhibit mitochondrial GPD2, a component of the glycerophosphate shuttle, thereby causing elevations of NADH (reductive stress) with consequent activation of the redox sensor CtBP2. We believe that this mechanism governs the increase of GDF15, which in turn inhibits intestinal tumorigenesis, likely inducing an antitumor immune response. We propose that specific combinations of biguanides, nutrients and/or novel drugs enhance this mechanism by elevating NADH content and GDF15 expression and may be exploited for therapeutic purposes in CRC.
The current project aims at elucidating these issues by 1) investigating the biguanide-GDF15 axis in preclinical tumor models of CRC, 2) defining its mode of action and 3) developing new approaches to exploit this mechanism for therapeutic purposes. Results from this study will provide invaluable information to understand the mechanism of action and conditions of usage of a widely studied class of metabolic drugs in CRC.
