Omaveloxolone Suppresses Cell Growth and Causes Cell Cycle Arrest by Downregulating CDC20 Expression in Glioblastoma Cells Both In Vitro and In Vivo.

in Journal of cellular and molecular medicine by Kuan-Ting Lee, Yi-Chiang Hsu, Ann-Shung Lieu, Chih-Lung Lin, Tai-Hsin Tsai

TLDR

  • Omaveloxolone, a synthetic oleanane triterpene, has antitumor activity against human glioblastoma cells by inducing cell cycle arrest and promoting cell death through the downregulation of CDC20 expression.

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.

Overview

  • The study investigates the antitumor activity of omaveloxolone, a synthetic oleanane triterpene, on human glioblastoma (GBM) cells.
  • The study aims to determine the underlying mechanism of omaveloxolone's antitumor activity and its potential as a treatment for GBM.
  • GBM cell lines (GBM8401 and U-87 MG cells) were exposed to different concentrations of omaveloxolone to study its effect on cell viability, morphology, and gene expression.

Comparative Analysis & Findings

  • Omaveloxolone showed selective cytotoxicity against human GBM cells, suppressing migration and invasion of these cancer cells.
  • Cell cycle arrest was induced through the downregulation of cell cycle-related genes, including CDC20, as revealed by next-generation sequencing.
  • In a xenograft tumor model, omaveloxolone decreased tumor volume and CDC20 expression, suggesting its potential as a treatment for GBM

Implications and Future Directions

  • The study suggests that omaveloxolone could be a potential drug candidate for GBM treatment, promoting GBM cell death through the downregulation of CDC20 expression.
  • Future studies should investigate the mechanism by which omaveloxolone downregulates CDC20 expression and explore the potential off-target effects of the compound.
  • Further studies are needed to determine the optimal dose and administration schedule for omaveloxolone in human clinical trials
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