Thursday, April 17, 2014
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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
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Phenformin was previously marketed to treat type 2 diabetes but was withdrawn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.
Published online April 17, 2014
Patent and licensing status
Birsoy, K. et al. Nature;
published online March 16, 2014;
Contact: David M. Sabatini, Whitehead Institute for
Biomedical Research, Cambridge, Mass.
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