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

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 ?-ketoglutarate (?-KG). We sought to therapeutically exploit this neoreaction in mutant IDH1 cells that require ?-KG derived from glutamine. Glutamine is converted to glutamate by glutaminase and further metabolized to ?-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 ?-KG. BPTES inhibited glutaminase activity, lowered glutamate and ?-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.

SUBMITTER: Seltzer MJ 

PROVIDER: S-EPMC3058858 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature