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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blotting, Western
  • Cell Line, Transformed
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Glioma / genetics
  • Glioma / metabolism
  • Glioma / pathology
  • Glutamic Acid / metabolism
  • Glutaminase / antagonists & inhibitors
  • Glutaminase / genetics
  • Glutaminase / metabolism*
  • Glutarates / metabolism
  • Humans
  • Isocitrate Dehydrogenase / genetics
  • Isocitrate Dehydrogenase / metabolism*
  • Ketoglutaric Acids / metabolism
  • Ketoglutaric Acids / pharmacology
  • Mutation*
  • RNA Interference
  • Sulfides / pharmacology
  • Thiadiazoles / pharmacology
  • Time Factors

Substances

  • Glutarates
  • Ketoglutaric Acids
  • Sulfides
  • Thiadiazoles
  • bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide
  • alpha-hydroxyglutarate
  • Glutamic Acid
  • Isocitrate Dehydrogenase
  • IDH1 protein, human
  • Glutaminase