Abstract
The recent discovery of mutations in metabolic enzymes has rekindled interest in harnessing the altered metabolism of cancer cells for cancer therapy. One potential drug target is isocitrate dehydrogenase 1 (IDH1), which is mutated in multiple human cancers. Here, we examine the role of mutant IDH1 in fully transformed cells with endogenous IDH1 mutations. A selective R132H-IDH1 inhibitor (AGI-5198) identified through a high-throughput screen blocked, in a dose-dependent manner, the ability of the mutant enzyme (mIDH1) to produce R-2-hydroxyglutarate (R-2HG). Under conditions of near-complete R-2HG inhibition, the mIDH1 inhibitor induced demethylation of histone H3K9me3 and expression of genes associated with gliogenic differentiation. Blockade of mIDH1 impaired the growth of IDH1-mutant--but not IDH1-wild-type--glioma cells without appreciable changes in genome-wide DNA methylation. These data suggest that mIDH1 may promote glioma growth through mechanisms beyond its well-characterized epigenetic effects.
Publication types
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
MeSH terms
- Animals
- Benzeneacetamides / administration & dosage
- Benzeneacetamides / pharmacology*
- Benzeneacetamides / toxicity
- Cell Differentiation* / drug effects
- Cell Transformation, Neoplastic
- Enzyme Inhibitors / pharmacology*
- Enzyme Inhibitors / toxicity
- Gene Expression Profiling
- Gene Expression Regulation, Neoplastic / drug effects
- Glioma / drug therapy
- Glioma / enzymology*
- Glioma / genetics
- Glioma / pathology*
- Glutarates / metabolism
- Histones / metabolism
- Imidazoles / administration & dosage
- Imidazoles / pharmacology*
- Imidazoles / toxicity
- Isocitrate Dehydrogenase / antagonists & inhibitors*
- Isocitrate Dehydrogenase / chemistry
- Isocitrate Dehydrogenase / genetics*
- Isocitrate Dehydrogenase / metabolism
- Methylation
- Mice
- Mice, SCID
- Mutant Proteins / antagonists & inhibitors
- Mutant Proteins / chemistry
- Mutant Proteins / metabolism
- Protein Multimerization
- RNA Interference
- Xenograft Model Antitumor Assays
Substances
- AGI-5198
- Benzeneacetamides
- Enzyme Inhibitors
- Glutarates
- Histones
- Imidazoles
- Mutant Proteins
- alpha-hydroxyglutarate
- Isocitrate Dehydrogenase
- IDH1 protein, human