Isocitrate dehydrogenase 1 -mutated cancers are sensitive to the green tea polyphenol epigallocatechin-3-gallate

Mutations in isocitrate dehydrogenase 1 ( ) occur in various types of cancer and induce metabolic alterations resulting from the neomorphic activity that causes production of -2-hydroxyglutarate ( 2-HG) at the expense of α-ketoglutarate (α-KG) and NADPH. To overcome metabolic stress induced by these alterations, -mutated ( ) cancers utilize rescue mechanisms comprising pathways in which glutaminase and glutamate dehydrogenase (GLUD) are involved. We hypothesized that inhibition of glutamate processing with the pleiotropic GLUD-inhibitor epigallocatechin-3-gallate (EGCG) would not only hamper 2-HG production, but also decrease NAD(P)H and α-KG synthesis in cancers, resulting in increased metabolic stress and increased sensitivity to radiotherapy. We performed C-tracing studies to show that HCT116 colorectal cancer cells with an knock-in allele depend more on glutaminolysis than on glycolysis for the production of -2-HG. We treated HCT116 cells, HCT116- cells, and HT1080 cells (carrying an mutation) with EGCG and evaluated 2-HG production, cell proliferation rates, and sensitivity to radiotherapy. Significant amounts of C from glutamate accumulate in 2-HG in HCT116- but not in HCT116- . Preventing glutamate processing in HCT116- cells with EGCG resulted in reduction of 2-HG production. In addition, EGCG treatment decreased proliferation rates of cells and at high doses sensitized cancer cells to ionizing radiation. Effects of EGCG in IDH-mutated cell lines were diminished by treatment with the IDH1 inhibitor AGI-5198. This work shows that glutamate can be directly processed into 2-HG and that reduction of glutamatolysis may be an effective and promising new treatment option for cancers.