Journal
BIOCHEMICAL PHARMACOLOGY
Volume 200, Issue -, Pages -Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2022.115037
Keywords
Micheliolide; Oxidative stress; Glutathione metabolism; Mitochondrial dysfunction; Glioblastoma; Leukemia
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Funding
- Accendatech Co., Ltd.
- National Natural Science Foundation of China [82073879, 81573282]
- Postdoctoral Science Foundation of China [2021M701791]
- Natural Science Foundation of Tianjin [21JCYBJC00190]
- National Science Fund for Distinguished Young Scholars [81625021]
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This study reveals the mechanism of MCL-induced oxidative stress in leukemia and glioblastoma cells, involving the mediation of reduced glutathione (GSH) and impairment of mitochondrial function. Furthermore, the inhibition of GSH biosynthesis by BSO enhances the therapeutic effect of MCL by suppressing GSH compensatory mechanism and promoting cancer cell oxidative stress.
Accumulating evidence has supported that targeting oxidative stress and metabolic alterations of cancer is an effective strategy to combat cancer. We previously reported that Dimethylaminomicheliolide (DMAMCL) and its active metabolite micheliolide (MCL) can cause oxidative stress and cell death in leukemia and glioblastoma. However, the detailed mechanism underlying MCL or DMAMCL triggered oxidative stress remains elusive. Herein, using leukemia HL60 cells and glioblastoma U118MG cells as models, we found that MCL-induced oxidative stress is mainly mediated by reduced glutathione (GSH). Overproduced reactive oxygen species (ROS) can lead to oxidative damage to mitochondrial, impairing the ability of the tricarboxylic acid (TCA) cycle and causing dysfunction of mitochondrial respiratory chain. On the other hand, the depletion of GSH activates GSH biosynthesis pathway and has possibility to give rise to more GSH to scavenge ROS in cancer cells. Targeting this redox and metabolic circuit, we identified L-buthionine sulfoximine (BSO), an inhibitor in GSH biosynthesis, as an agent that can enhance MCL regimen to inhibit GSH compensatory event and thereby further facilitate cancer cell oxidative stress. Together, these results illustrate that targeting redox and metabolic pathway by MCL/DMAMCL combination with BSO is a potent therapeutic intervention for the treatments of glioblastoma and acute-myelocytic leukemia.
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