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Cancer Res. 2010 Nov 15;70(22):8981-7. doi: 10.1158/0008-5472.CAN-10-1666. Epub 2010 Nov 2.

Inhibition of glutaminase preferentially slows growth of glioma cells with mutant IDH1.

Author information

1
Department of Neurosurgery, and Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.

Abstract

Mutation at the R132 residue of isocitrate dehydrogenase 1 (IDH1), frequently found in gliomas and acute myelogenous leukemia, creates a neoenzyme that produces 2-hydroxyglutarate (2-HG) from α-ketoglutarate (α-KG). We sought to therapeutically exploit this neoreaction in mutant IDH1 cells that require α-KG derived from glutamine. Glutamine is converted to glutamate by glutaminase and further metabolized to α-KG. Therefore, we inhibited glutaminase with siRNA or the small molecule inhibitor bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES) and found slowed growth of glioblastoma cells expressing mutant IDH1 compared with those expressing wild-type IDH1. Growth suppression of mutant IDH1 cells by BPTES was rescued by adding exogenous α-KG. BPTES inhibited glutaminase activity, lowered glutamate and α-KG levels, and increased glycolytic intermediates while leaving total 2-HG levels unaffected. The ability to selectively slow growth in cells with IDH1 mutations by inhibiting glutaminase suggests a unique reprogramming of intermediary metabolism and a potential therapeutic strategy.

PMID:
21045145
PMCID:
PMC3058858
DOI:
10.1158/0008-5472.CAN-10-1666
[Indexed for MEDLINE]
Free PMC Article

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