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 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.

• Authors: 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
• Journal: Cancer research (Cancer Res) Vol. 70 Issue 22 Pg. 8981-7 (Nov 15 2010) ISSN: 1538-7445 [Electronic] United States
• PMID: 21045145 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010 AACR.

Chemical References

• 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

Topics

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