Inhibition of glutaminase preferentially slows growth of glioma cells with mutant IDH1.
Cancer Res
; 70(22): 8981-7, 2010 Nov 15.
Article
em En
| MEDLINE
| ID: mdl-21045145
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Glutaminase
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Isocitrato Desidrogenase
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Mutação
Limite:
Humans
Idioma:
En
Ano de publicação:
2010
Tipo de documento:
Article