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

Tom H. Peeters†,
Krissie Lenting†,
Vincent Breukels,
Sanne A. M. van Lith,
Corina N. A. M. van den Heuvel,
Remco Molenaar,
Arno van Rooij,
Ron Wevers,
Paul N. Span,
Arend Heerschap and
William P. J. LeendersEmail author

†Contributed equally

Cancer & Metabolism20197:4

https://doi.org/10.1186/s40170-019-0198-7

Received: 1 November 2018
Accepted: 9 April 2019
Published: 20 May 2019

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 (IDHmut) 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 IDHmut 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 IDH1R132H knock-in allele depend more on glutaminolysis than on glycolysis for the production of D-2-HG. We treated HCT116 cells, HCT116-IDH1R132H cells, and HT1080 cells (carrying an IDH1R132C 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-IDH1wt/R132H but not in HCT116-IDH1wt/wt. Preventing glutamate processing in HCT116-IDH1wt/R132H cells with EGCG resulted in reduction of D-2-HG production. In addition, EGCG treatment decreased proliferation rates of IDH1mut 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 IDH1mut 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 IDHmut cancers.