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TP 227b Induction of mesothelioma cell apoptosis by GANT61, a small molecule inhibitor of GLI transcription factors: Evidence for redox-driven cytotoxicity
Journal article   Peer reviewed

TP 227b Induction of mesothelioma cell apoptosis by GANT61, a small molecule inhibitor of GLI transcription factors: Evidence for redox-driven cytotoxicity

C.B. Lim, C.M. Prêle, P.G. Arthur, J. Creaney, D.N. Watkins, S. Baltic, P.J. Thompson and S.E. Mutsaers
Respirology, Vol.20
2015
DOI: https://doi.org/10.1111/resp.12495_17
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Abstract

Background: Although it has been shown that Gli transcription factors are the major intracellular target of the small molecule inhibitor GANT61, the underlying mechanism by which GANT61 inhibits cancer cell growth remains unclear. In this study, we aimed to elucidate the mechanisms that underlie the induction of mesothelioma cell apoptosis by GANT61. Method: Human mesothelioma cells were treated with GANT61. Levels of apoptosis and reactive oxygen species (ROS) were quantified by flow cytometry. Results: Our study showed that GANT61 induces growth inhibition and apoptosis in mesothelioma cells through the induction of oxidative stress. Exposure of mesothelioma cells to GANT61 resulted in the rapid production of ROS. Quenching of ROS by the antioxidants N-acetylcysteine and L-glutathione blocked the induction of apoptosis and depolarization of mitochondrial membrane potential by GANT61, indicating that ROS overproduction is the primary driver for the pro-apoptotic activity of GANT61. Although GANT61 could inhibit Gli transcriptional activity, the inhibition of Gli was not sufficient to initiate apoptosis in mesothelioma cells. Further study revealed that the ROS species generated was superoxide from the mitochondria, and that mitochondrial electron transport chain inhibition by rotenone significantly suppressed the pro-apoptotic effect of GANT61. Conclusion: Our study provides evidence that GANT61 is a potent anti-mesothelioma therapeutic agent, which induces apoptosis in mesothelioma cells through the generation of mitochondrial superoxide.

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