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

Abstract

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.

Energy Metabolism in IDH1 Wild-Type and IDH1-Mutated Glioblastoma Stem Cells: A Novel Target for Therapy?

“…As explained above, metformin and phenformin inhibit complex I of the electron transport chain of OXPHOS and glutamate dehydrogenase, whereas chloroquine inhibits glutamate dehydrogenase ( Figure 5 ) [ 10 , 61 ]. EGCG, a major polyphenol flavonoid in green tea [ 78 ], reduces D-2-HG production and the proliferation of IDH1 mt glioblastoma cells [ 79 ]. In glioblastoma patients, EGCG seems effective only when used in large quantities as an adjuvant during radiotherapy and temozolomide chemotherapy [ 78 ].…”

A D-2-hydroxyglutarate biosensor based on specific transcriptional regulator DhdR

“…As shown in Fig. 5i, the D-2-HG biosensor B D2HG -1 could detect the increase in the levels of D-2-HG in the cell culture medium during the growth of HEK293FT cells transfected with IDH1/R132H and of HT1080 cells, a fibrosarcoma cell line carrying an IDH1/R132C mutation 30 . No D-2-HG was detected in the cell culture medium of HEK293FT cells.…”

Glutaminolysis dynamics during astrocytoma progression correlates with tumor aggressiveness

“…Metabolomic studies of IDH1 mutant cells have revealed alterations in Gln, fatty acid, and citrate synthesis pathways [ 59 , 60 ]. IDH1 mutation was shown to convert α–KG to D–2–hydroxyglutarate, which due to its structural similarities acts as a competitive inhibitor reducing the activity of α–KG–processing enzymes [ 61 ]. As feedback, α–KG is replenished by glutaminolysis and TCA cycle, which leads to a decrease in Gln and Glu levels [ 62 ].…”

“…The downregulated expression is represented by blue thermometers, upregulated by red thermometers, and the non-significant differential expression in gray. Red arrows represent the activation of the pathway and blue arrows represent the inactivation of the pathway shown to convert α-KG to D-2-hydroxyglutarate, which due to its structural similarities acts as a competitive inhibitor reducing the activity of α-KG-processing enzymes [61]. As feedback, α-KG is replenished by glutaminolysis and TCA cycle, which leads to a decrease in Gln and Glu levels [62].…”