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 ¹³C-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 ¹³C 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.