Inhibition of glutaminase preferentially slows growth of glioma cells with mutant IDH1.
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.
Department of Neurosurgery, and Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
Meghan J
MJ
Seltzer
Bryson D
BD
Bennett
Avadhut D
AD
Joshi
Ping
P
Gao
Ajit G
AG
Thomas
Dana V
DV
Ferraris
Takashi
T
Tsukamoto
Camilo J
CJ
Rojas
Barbara S
BS
Slusher
Joshua D
JD
Rabinowitz
Chi V
CV
Dang
Gregory J
GJ
Riggins
D015153:Blotting, Western; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005910:Glioma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018698:Glutamic Acid / Q000378:metabolism; D005972:Glutaminase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005977:Glutarates / Q000378:metabolism; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D007656:Ketoglutaric Acids / Q000378:metabolism / Q000494:pharmacology; D009154:Mutation; D034622:RNA Interference; D013440:Sulfides / Q000494:pharmacology; D013830:Thiadiazoles / Q000494:pharmacology; D013997:Time Factors
D005977:Glutarates; D007656:Ketoglutaric Acids; D013440:Sulfides; D013830:Thiadiazoles; C523193:bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide; C019417:alpha-hydroxyglutarate; D018698:Glutamic Acid; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D005972:Glutaminase