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

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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

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Metformin
Hypoglycemic Agents
Growth
Neoplasms
HCT116 Cells
AMP-Activated Protein Kinases
Autophagy
Therapeutics
Apoptosis
Poisons
Oxidative Phosphorylation
Glycolysis
Electron Transport
Heterografts
Colonic Neoplasms
Fatty Acids
Embryonic Structures
Fibroblasts
Cell Line
Food

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth. / Buzzai, Monica; Jones, Russell G.; Amaravadi, Ravi K.; Lum, Julian J.; DeBerardinis, Ralph J.; Zhao, Fangping; Viollet, Benoit; Thompson, Craig B.

In: Cancer Research, Vol. 67, No. 14, 15.07.2007, p. 6745-6752.

Research output: Contribution to journalArticle

Buzzai, M, Jones, RG, Amaravadi, RK, Lum, JJ, DeBerardinis, RJ, Zhao, F, Viollet, B & Thompson, CB 2007, 'Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth', Cancer Research, vol. 67, no. 14, pp. 6745-6752. https://doi.org/10.1158/0008-5472.CAN-06-4447
Buzzai, Monica ; Jones, Russell G. ; Amaravadi, Ravi K. ; Lum, Julian J. ; DeBerardinis, Ralph J. ; Zhao, Fangping ; Viollet, Benoit ; Thompson, Craig B. / Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth. In: Cancer Research. 2007 ; Vol. 67, No. 14. pp. 6745-6752.
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