Blockade of Glutathione Metabolism in IDH1-Mutated Glioma

  • Mol Cancer Ther. 2020 Jan;19(1):221-230. doi: 10.1158/1535-7163.MCT-19-0103.
Xiaoying Tang  1 ,  Xiao Fu  1  2 ,  Yang Liu  2 ,  Di Yu  2 ,  Sabrina J Cai  2 ,  Chunzhang Yang  3
Affiliations
  • 1. School of Life Science and Technology, Beijing Institute of Technology, Beijing, China.
  • 2. Neuro-Oncology Branch, Center for Cancer Research, NCI, Bethesda, Maryland.
  • 3. Neuro-Oncology Branch, Center for Cancer Research, NCI, Bethesda, Maryland. [email protected].
PMID: 31548295 DOI: 10.1158/1535-7163.MCT-19-0103
Abstract

Mutations in genes encoding isocitrate dehydrogenases (IDH) 1 and 2 are common cancer-related genetic abnormalities. Malignancies with mutated IDHs exhibit similar pathogenesis, metabolic pattern, and resistance signature. However, an effective therapy against IDH1-mutated solid tumor remains unavailable. In this study, we showed that acquisition of IDH1 mutation results in the disruption of NADP+/NADPH balance and an increased demand for glutathione (GSH) metabolism. Moreover, the nuclear factor erythroid 2-related factor 2 (Nrf2) plays a key protective role in IDH1-mutated cells by prompting GSH synthesis and Reactive Oxygen Species scavenging. Pharmacologic inhibition of the Nrf2/GSH pathway via brusatol administration exhibited a potent tumor suppressive effect on IDH1-mutated Cancer in vitro and in vivo Our findings highlight a possible therapeutic strategy that could be valuable for IDH1-mutated Cancer treatment.

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