Triptolide suppresses IDH1-mutated malignancy via Nrf2-driven glutathione metabolism | Zendy

Di Yu | Zendy; Yang Liu | Zendy; Yiqiang Zhou | Zendy; Victor RuizRodado | Zendy; Mioara Larion | Zendy; Guowang Xu | Zendy; Chunzhang Yang | Zendy

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Triptolide suppresses IDH1-mutated malignancy via Nrf2-driven glutathione metabolism

Author(s) -

Di Yu,

Yang Liu,

Yiqiang Zhou,

Victor RuizRodado,

Mioara Larion,

Guowang Xu,

Chunzhang Yang

Publication year - 2020

Publication title -

proceedings of the national academy of sciences

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 5.011

H-Index - 771

eISSN - 1091-6490

pISSN - 0027-8424

DOI - 10.1073/pnas.1913633117

Subject(s) - idh1 , triptolide , cancer research , mutation , blockade , biology , chemistry , apoptosis , gene , genetics , receptor

Significance IDH1 mutation is a common genetic abnormality in human malignancies, whereas selective therapeutics for IDH1-mutated malignancies remain unavailable. Our present study reveals that IDH1-mutated cancer cells exhibit addiction to Nrf2-governed antioxidative pathways. Blockade of Nrf2 transcriptional activity achieved synergistic lethality with a neomorphic IDH1 mutation. We also showed that triptolide serves as a potent Nrf2 inhibitor, which inhibited Nrf2 transcriptional activity and led to apoptotic changes in IDH1-mutated cells via redox catastrophe. We believe that our findings highlight the broad scope and significance of Nrf2 blockade as a therapeutic strategy and provide an actionable strategy for IDH1-mutated malignancies.

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