Systemic Treatment with the Antidiabetic Drug Metformin Selectively Impairs P53-deficient Tumor Cell Growth.
From: Abramson Family Cancer Research Institute, Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Cancer research
- Publish Date: Jul 2007
- ISSN: 0008-5472
- Volume: 67
- Issue: 14
- Pages: 6745-52
- Medium: Print
- Language: English
- Citation (JAMA): Buzzai Monica, Jones Russell G, Amaravadi Ravi K, et al. Systemic Treatment with the Antidiabetic Drug Metformin Selectively Impairs P53-deficient Tumor Cell Growth.. Cancer Res. Jul 2007;67:6745-52
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 beta-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.
Mesh Headings (Keywords): Animals, Apoptosis, Cell Line, Tumor, Cell Proliferation, Fibroblasts, Humans, Hypoglycemic Agents, Metformin, Mice, Mice, Transgenic, Mitochondria, Multienzyme Complexes, Neoplasm Transplantation, Neoplasms, Protein-Serine-Threonine Kinases, Tumor Suppressor Protein p53
Check for Full Text / PubMed Unique Identifier (PMID): 17638885
This abstract is part of PubMed, a service of the U.S. National Library of Medicine. PubMed includes more than 17 million citations from MEDLINE and other life science journals for biomedical articles. See Copyright and Disclaimers.
Linked medical terms appearing on this page are added by Healia to help readers find more information and are not part of the original PubMed document.
The data herein was last updated on July 8th, 2008 and may not reflect the most current and accurate data available from NLM.