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

Background Mutations in isocitrate dehydrogenase 1 ( IDH1 ) occur in various types of cancer and induce metabolic alterations resulting from the neomorphic activity that causes production of D -2-hydroxyglutarate ( D- 2-HG) at the expense of α-ketoglutarate (α-KG) and NADPH. To overcome metabolic stress induced by these alterations, IDH -mutated ( IDH mut ) 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 D- 2-HG production, but also decrease NAD(P)H and α-KG synthesis in IDH mut cancers, resulting in increased metabolic stress and increased sensitivity to radiotherapy. Methods We performed 13 C-tracing studies to show that HCT116 colorectal cancer cells with an IDH1 R132H knock-in allele depend more on glutaminolysis than on glycolysis for the production of D -2-HG. We treated HCT116 cells, HCT116- IDH1 R132H cells, and HT1080 cells (carrying an IDH1 R132C mutation) with EGCG and evaluated D- 2-HG production, cell proliferation rates, and sensitivity to radiotherapy. Results Significant amounts of 13 C from glutamate accumulate in D- 2-HG in HCT116- IDH1 wt/R132H but not in HCT116- IDH1 wt/wt . Preventing glutamate processing in HCT116- IDH1 wt/R132H cells with EGCG resulted in reduction of D- 2-HG production. In addition, EGCG treatment decreased proliferation rates of IDH1 mut 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 mut inhibitor AGI-5198. Conclusions This work shows that glutamate can be directly processed into D- 2-HG and that reduction of glutamatolysis may be an effective and promising new treatment option for IDH mut cancers.