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

¹ Abramson Family Cancer Research Institute, Department of Cancer Biology; ² Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania; ³ Division of Child Development, Rehabilitation Medicine and Metabolic Disease, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; ⁴ Institut Cochin, Université Paris Descartes, Centre National de la Recherche Scientifique (UMR 8104); and ⁵ Inserm, U567, Paris, France

Requests for reprints: Craig B. Thompson, Abramson Family Cancer Research Institute, Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104. Phone: 215-746-5515; Fax: 215-746-5511; E-mail: craig{at}mail.med.upenn.edu.

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^–/–. Treatment with metformin selectively suppressed the tumor growth of HCT116 p53^–/– xenografts. Following treatment 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 treatment as an indirect activator of AMP-activated protein kinase (AMPK). Treatment 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. Treatment with either metformin or AICAR also led to enhanced fatty acid ß-oxidation in p53^+/+ MEFs, but not in p53^–/– MEFs. However, the magnitude of induction was significantly lower in metformin-treated cells, as metformin treatment 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 treatment 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]

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