English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Global: Zendy Plus annual

Presents the access of premium content as premium feature

Premium Content

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Global: Zendy Tools annual

Global: Zendy Free Plan

Global: Zendy Tools monthly

Global: Zendy Plus monthly

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.

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