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Mol Cancer Ther. 2019 Sep 23. pii: molcanther.0103.2019. doi: 10.1158/1535-7163.MCT-19-0103. [Epub ahead of print]

Blockade of glutathione metabolism in IDH1-mutated glioma.

Author information

1
School of Life Science and Technology, Beijing Institute of Technology.
2
Neuro-Oncology Branch, National Cancer Institute.
3
Neuro-Oncology Branch, National Cancer Institute yangc2@nih.gov.

Abstract

Mutations in genes encoding isocitrate dehydrogenases (IDHs) 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 the present study, we showed that acquisition of IDH1 mutation results in the disruption of NADP+/NADPH balance and an increased demand for glutathione metabolism. Moreover, the nuclear factor erythroid 2-related factor 2 (Nrf2) plays a key protective role in IDH1-mutated cells by prompting glutathione synthesis and ROS scavenging. Pharmacological inhibition of the Nrf2/glutathione 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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