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Mitochondrial DNA (mtDNA) mutations and impaired glucose utilization as markers of sensitivity to biguanides in cancer

Cell culture studies suggest mutations in mtDNA and impaired glucose utilization could be useful as markers to help predict cancer sensitivity to biguanides, which inhibit oxidative phosphorylation. Biguanides such as metformin and phenformin are diabetes drugs that inhibit the growth of some cancers, but markers to predict cancer sensitivity to these drugs have not been discovered. In a panel of human cancer cell lines cultured under low-glucose conditions, metabolic profiling, DNA sequencing and RNAi screening showed that impaired glucose utilization and mutations in mtDNA-encoded genes for the core complex I subunits of mitochondria were associated with increased sensitivity to inhibition of oxidative phosphorylation. In low-glucose culture conditions, cancer cell lines with impaired glucose utilization or those carrying mutations in mtDNA showed 5- to 20-fold increased sensitivity to phenformin compared with control cancer cell lines and an immortalized B cell line. Next steps could include validating these markers of biguanide sensitivity in a larger patient cohort and then developing a patient screening assay.
Metformin is a generic drug used to treat type 2 diabetes.
Phenformin was previously marketed to treat type 2 diabetes but was withdrawn in 1978 because of a high risk for lactic acidosis.

SciBX 7(15); doi:10.1038/scibx.2014.446
Published online April 17, 2014

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Birsoy, K. et al. Nature; published online March 16, 2014;
Contact: David M. Sabatini, Whitehead Institute for Biomedical Research, Cambridge, Mass.