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A rational foundation for micheliolide-based combination strategy by targeting redox and metabolic circuit in cancer
Jianshuang Guo1, Kaihui Liu1, Jiyan Wang1
1State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, College of Chemistry, Nankai University, Haihe Education Park, 38 Tongyan Road, Tianjin 300353, China.
Abstract:
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.
Insights
Micheliolide (MCL) triggers cancer cell death by causing oxidative stress, primarily through glutathione (GSH) depletion. Combining MCL with L-buthionine sulfoximine (BSO) enhances this effect, offering a potential therapy for glioblastoma and leukemia.
Area of Science:
- Oncology
- Cancer Metabolism
- Redox Biology
Background:
- Targeting cancer's oxidative stress and metabolic pathways is a promising therapeutic strategy.
- Dimethylaminomicheliolide (DMAMCL) and its metabolite micheliolide (MCL) induce oxidative stress and cell death in leukemia and glioblastoma.
- The precise mechanism of MCL/DMAMCL-induced oxidative stress requires further elucidation.
Purpose of the Study:
- To investigate the detailed mechanism of MCL-induced oxidative stress in leukemia and glioblastoma cells.
- To identify potential therapeutic strategies by targeting the identified redox and metabolic pathways.
Main Methods:
- Utilized leukemia HL60 and glioblastoma U118MG cell lines as experimental models.
- Assessed the role of reduced glutathione (GSH) in mediating MCL-induced oxidative stress.
- Investigated the impact of oxidative stress on mitochondrial function, including the tricarboxylic acid (TCA) cycle and respiratory chain.
- Evaluated the efficacy of L-buthionine sulfoximine (BSO), a GSH biosynthesis inhibitor, in combination with MCL.
Main Results:
- MCL-induced oxidative stress is primarily mediated by the depletion of reduced glutathione (GSH).
- Elevated reactive oxygen species (ROS) damage mitochondria, impairing the TCA cycle and respiratory chain function.
- GSH depletion activates its own biosynthesis pathway, creating a compensatory mechanism to scavenge ROS.
- The combination of MCL/DMAMCL with BSO effectively inhibits GSH compensatory pathways, amplifying oxidative stress in cancer cells.
Conclusions:
- MCL-induced oxidative stress involves GSH depletion and subsequent mitochondrial dysfunction.
- Targeting the GSH biosynthesis pathway with BSO can potentiate the anti-cancer effects of MCL/DMAMCL.
- The combination of MCL/DMAMCL and BSO represents a potent therapeutic approach for glioblastoma and acute-myeloid leukemia by targeting redox and metabolic circuits.
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