Glutaminase Inhibitors Slow Growth of Some Brain Tumors

Some types of cancers display a mutation in a gene that codes for an enzyme critical to the molecular pathway that converts sugars to energy, a mutation that may represent a target for directed chemotherapy.

Isocitrate dehydrogenase 1(IDH1), is an enzyme that participates in the citric acid cycle. It catalyzes the third step of the cycle: the oxidative decarboxylation of isocitrate, producing alpha-ketoglutarate (alpha-KG) and carbon dioxide while converting NAD+ to NADH. This is a two-step process, which involves oxidation of isocitrate (a secondary alcohol) to oxalosuccinate (a ketone), followed by the decarboxylation of the carboxyl group beta to the ketone, forming alpha-KG.

Recent studies have shown that a mutation at the R132 residue of IDH1 occurs in more than 70% of three common types of gliomas: low-grade astrocytomas, oligodendrogliomas, and secondary glioblastomas as well as in acute myelogenous leukemias. These mutant IDH1 cells require alpha-KG derived from glutamine. Glutamine is converted to glutamate by glutaminase and further metabolized to alpha-KG.

Investigators at Johns Hopkins University (Baltimore, MD, USA) inhibited glutaminase with siRNA or the small molecule inhibitor bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES). They reported in the November 15, 2010, issue of the journal Cancer Research that inhibition of glutaminase slowed growth of glioblastoma cells expressing mutant IDH1 compared with those expressing wild-type IDH1. Growth suppression of mutant IDH1 cells by BPTES could be reversed by adding exogenous alpha-KG. BPTES inhibited glutaminase activity, lowered glutamate and alpha-KG levels, and increased glycolytic intermediates.

"The glutaminase inhibitor we tested does not completely stop cancer cell growth, but slows it down,” said senior author Dr. Gregory Riggins, professor of neurosurgery research at Johns Hopkins University. "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.”

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