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Omaveloxolone Suppresses Cell Growth and Causes Cell Cycle Arrest by Downregulating CDC20 Expression in Glioblastoma
Kuan-Ting Lee1, Yi-Chiang Hsu2, Ann-Shung Lieu1,3,4
1Graduate Institutes of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Abstract:
Omaveloxolone is a synthetic oleanane triterpene with considerable antitumor activity. It induces human glioblastoma (GBM) cell death in vitro and in vivo, but the underlying mechanism remains to be determined. In this study, GBM cell lines (GBM8401 and U-87 MG cells) were exposed to different concentrations of omaveloxolone (0, 600, 800 and 1000 nM). A cell viability assay was conducted using the PrestoBlue Cell Viability Reagent. Three-dimensional microscopy revealed changes in cell morphology. Cell cycle, apoptosis and mitochondrial membrane potential were tested using flow cytometry. The expression levels of cell cycle-related proteins and genes were determined through Western blotting and next-generation sequencing, respectively. The results indicated that omaveloxolone had significant selective cytotoxicity against human GBM cells and suppressed the migration and invasion of these cancer cells. It also caused cell cycle arrest through the downregulation of cell cycle-related genes, including cell division cycle 20 homologue (CDC20), as revealed by next-generation sequencing. In a xenograft tumour model, omaveloxolone decreased tumour volume and CDC20 expression. Taken together, these findings suggest that omaveloxolone is a potential drug candidate for GBM treatment by promoting GBM cell death through the downregulation of CDC20 expression.
Insights
Omaveloxolone effectively reduces glioblastoma (GBM) tumor growth and induces cancer cell death. This is achieved by downregulating cell division cycle 20 homologue (CDC20) expression, suggesting potential for GBM treatment.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Omaveloxolone, a synthetic oleanane triterpene, exhibits antitumor properties.
- The precise mechanism by which omaveloxolone induces glioblastoma (GBM) cell death requires elucidation.
Purpose of the Study:
- To investigate the mechanism of omaveloxolone-induced GBM cell death.
- To evaluate the efficacy of omaveloxolone in preclinical GBM models.
Main Methods:
- Exposure of GBM cell lines (GBM8401, U-87 MG) to omaveloxolone.
- Cell viability, morphology, cell cycle, apoptosis, and mitochondrial membrane potential assays.
- Western blotting and next-generation sequencing for gene and protein expression analysis.
- Evaluation in a xenograft tumor model.
Main Results:
- Omaveloxolone demonstrated selective cytotoxicity against human GBM cells, inhibiting migration and invasion.
- Omaveloxolone induced cell cycle arrest by downregulating cell cycle-related genes, notably cell division cycle 20 homologue (CDC20).
- In vivo, omaveloxolone reduced tumor volume and decreased CDC20 expression in a xenograft model.
Conclusions:
- Omaveloxolone exhibits potential as a therapeutic agent for glioblastoma.
- The drug promotes GBM cell death, partly through the downregulation of CDC20 expression.
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