Systemic Results with the Antidiabetic Drug Metformin Selectively Impairs p53-Deficient Tumor Cell Growth

The effect of the antidiabetic drug metformin on tumor growth was investigated using the paired isogenic colon cancer cell lines HCT116 p53^+/+ and HCT116 p53^−/−. Results with metformin selectively suppressed the tumor growth of HCT116 p53^−/− xenografts. Following results with metformin, we detected increased apoptosis in p53^−/− tumor sections and an enhanced susceptibility of p53^−/− cells to undergo apoptosis in vitro when subject to nutrient deprivation. Metformin is proposed to function in diabetes results as an indirect activator of AMP-activated protein kinase (AMPK). Results with AICAR, another AMPK activator, also showed a selective ability to inhibit p53^−/− tumor growth in vivo. In the presence of either of the two drugs, HCT116 p53^+/+ cells, but not HCT116 p53^−/− cells, activated autophagy. A similar p53-dependent induction of autophagy was observed when nontransformed mouse embryo fibroblasts were treated. Results with either metformin or AICAR also led to enhanced fatty acid β-oxidation in p53^+/+ MEFs, but not in p53^−/− MEFs. However, the magnitude of induction was significantly lower in metformin-treated cells, as metformin results also suppressed mitochondrial electron transport. Metformin-treated cells compensated for this suppression of oxidative phosphorylation by increasing their rate of glycolysis in a p53-dependent manner. Together, these data suggest that metformin results forces a metabolic conversion that p53^−/− cells are unable to execute. Thus, metformin is selectively toxic to p53-deficient cells and provides a potential mechanism for the reduced incidence of tumors observed in patients being treated with metformin. [Cancer Res 2007;67(14):6745–52]