Blockade of Glutathione Metabolism in IDH1-Mutated Glioma

被引：71

作者：

Tang, Xiaoying ^{[1
]}

Fu, Xiao ^{[1
,2
]}

Liu, Yang ^{[2
]}

Yu, Di ^{[2
]}

Cai, Sabrina J. ^{[2
]}

Yang, Chunzhang ^{[2
]}

机构：

[1] Beijing Inst Technol, Sch Life Sci & Technol, Beijing, Peoples R China

[2] NCI, Neurooncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA

来源：

MOLECULAR CANCER THERAPEUTICS | 2020年 / 19卷 / 01期

关键词：

ISOCITRATE DEHYDROGENASE; OXIDATIVE STRESS; GAUCHER-DISEASE; INHIBITION; MUTATIONS; IDH1; NRF2; ACTIVATION; GROWTH; CELLS;

D O I：

10.1158/1535-7163.MCT-19-0103

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：221 / 230

页数：10

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