PT  - JOURNAL ARTICLE
AU  - Tang, Xiaoying
AU  - Fu, Xiao
AU  - Liu, Yang
AU  - Yu, Di
AU  - Cai, Sabrina J.
AU  - Yang, Chunzhang
TI  - Blockade of Glutathione Metabolism in <em>IDH1</em>-Mutated Glioma
AID  - 10.1158/1535-7163.MCT-19-0103
DP  - 2019 Sep 23
TA  - Molecular Cancer Therapeutics
4099  - http://mct.aacrjournals.org/content/early/2019/12/20/1535-7163.MCT-19-0103.short
4100  - http://mct.aacrjournals.org/content/early/2019/12/20/1535-7163.MCT-19-0103.full
AB  - 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.