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Inhibition of glutaminase selectively suppresses the growth of primary acute myeloid leukemia cells with IDH mutations.

Abstract
The incidence of mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) in de novo acute myeloid leukemia (AML) is approximately 20%. These mutations result in distinct metabolic characteristics including dependency of cancer cells on glutamine as the main source for α-ketoglutarate, which is consumed by leukemia cells to produce a cancer-derived metabolite, 2-hydroxyglutarate. We sought to exploit this glutamine addiction therapeutically in mutant IDH primary AML cells from patients by measuring cell growth after exposure to a small molecule glutaminase inhibitor, BPTES. We found that BPTES only suppressed the growth of AML cells expressing mutant IDH compared with those expressing wild type IDH. This study lays the groundwork for strategies to target a specific subtype of AML metabolically with IDH mutations with a unique reprogramming of intermediary metabolism that culminates in glutamine dependency of cancer cells for survival.
AuthorsAshkan Emadi, Sung Ah Jun, Takashi Tsukamoto, Amir T Fathi, Mark D Minden, Chi V Dang
JournalExperimental hematology (Exp Hematol) Vol. 42 Issue 4 Pg. 247-51 (Apr 2014) ISSN: 1873-2399 [Electronic] Netherlands
PMID24333121 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2014 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.
Chemical References
  • Sulfides
  • Thiadiazoles
  • bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide
  • IDH2 protein, human
  • Isocitrate Dehydrogenase
  • IDH1 protein, human
  • Glutaminase
Topics
  • Cell Line, Tumor
  • Cell Survival (drug effects, genetics)
  • Female
  • Glutaminase (antagonists & inhibitors, genetics, metabolism)
  • Humans
  • Isocitrate Dehydrogenase (genetics, metabolism)
  • Leukemia, Myeloid, Acute (drug therapy, enzymology, genetics)
  • Male
  • Mutation
  • Sulfides (pharmacology)
  • Thiadiazoles (pharmacology)

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