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

Meghan J. Seltzer, Bryson D. Bennett, Avadhut D. Joshi, Ping Gao, Ajit G. Thomas, Dana V. Ferraris, Takashi Tsukamoto, Camilo J. Rojas, Barbara S. Slusher, Joshua D. Rabinowitz, Chi V. Dang, Gregory J. Riggins

Research output: Contribution to journalArticle

322 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)8981-8987
Number of pages7
JournalCancer Research
Volume70
Issue number22
DOIs
StatePublished - Nov 15 2010

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Inhibition of glutaminase preferentially slows growth of glioma cells with mutant IDH1'. Together they form a unique fingerprint.

  • Cite this

    Seltzer, M. J., Bennett, B. D., Joshi, A. D., Gao, P., Thomas, A. G., Ferraris, D. V., Tsukamoto, T., Rojas, C. J., Slusher, B. S., Rabinowitz, J. D., Dang, C. V., & Riggins, G. J. (2010). Inhibition of glutaminase preferentially slows growth of glioma cells with mutant IDH1. Cancer Research, 70(22), 8981-8987. https://doi.org/10.1158/0008-5472.CAN-10-1666