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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s40170-019-0198-7) contains supplementary material, which is available to authorized users.