期刊
MOLECULAR CANCER THERAPEUTICS
卷 19, 期 1, 页码 221-230出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-19-0103
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资金
- Intramural Research Program of the NIH, NCI, CCR
- NATIONAL CANCER INSTITUTE [ZIABC011684, ZIABC011761] Funding Source: NIH RePORTER
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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