Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth

Monica Buzzai, Russell G. Jones, Ravi K. Amaravadi, Julian J. Lum, Ralph J. DeBerardinis, Fangping Zhao, Benoit Viollet, Craig B. Thompson

Research output: Contribution to journalArticle

682 Scopus citations

Abstract

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 β-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.

Original languageEnglish (US)
Pages (from-to)6745-6752
Number of pages8
JournalCancer research
Volume67
Issue number14
DOIs
StatePublished - Jul 15 2007

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth'. Together they form a unique fingerprint.

  • Cite this

    Buzzai, M., Jones, R. G., Amaravadi, R. K., Lum, J. J., DeBerardinis, R. J., Zhao, F., Viollet, B., & Thompson, C. B. (2007). Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth. Cancer research, 67(14), 6745-6752. https://doi.org/10.1158/0008-5472.CAN-06-4447