期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 117, 期 18, 页码 9964-9972出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1913633117
关键词
triptolide; IDH1 mutation; Nrf2; glutathione; reactive oxygen species
资金
- Intramural Research Program of the NIH, NCI
- National Natural Science Foundation of China [81472374]
- NATIONAL CANCER INSTITUTE [ZIABC011710, ZIABC011709, ZIABC011761] Funding Source: NIH RePORTER
Isocitrate dehydrogenase (IDH) mutation is a common genetic abnormality in human malignancies characterized by remarkable metabolic reprogramming. Our present study demonstrated that IDH1-mutated cells showed elevated levels of reactive oxygen species and higher demands on Nrf2-guided glutathione de novo synthesis. Our findings showed that triptolide, a diterpenoid epoxide from Tripterygium wilfordii, served as a potent Nrf2 inhibitor, which exhibited selective cytotoxicity to patient-derived IDH1-mutated glioma cells in vitro and in vivo. Mechanistically, triptolide compromised the expression of GCLC, GCLM, and SLC7A11, which disrupted glutathione metabolism and established synthetic lethality with reactive oxygen species derived from IDH1 mutant neomorphic activity. Our findings highlight triptolide as a valuable therapeutic approach for IDH1-mutated malignancies by targeting the Nrf2-driven glutathione synthesis pathway.
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