Abstract 4893: XIAP downregulation accompanies inhibition of melanoma xenograft growth by mebendazole

Abstract

Abstract Background: Melanoma's intrinsic resistance to therapy has been attributed to modulation of cellular survival pathways including apoptosis. We originally reported that mebendazole (MBZ), which acts as a microtubule-disrupting agent, is a potent inducer of apoptosis in melanoma cells in vitro via a Bcl-2 dependent mechanism (Molecular Cancer Research, 2008). Here, we show that MBZ is also able to effectively modulate another key anti-apoptotic factor, XIAP, to promote melanoma apoptosis both in vitro and in vivo. Methodology: Safety and efficacy of mebendazole was assessed using a human melanoma xenograft model established from M-14 cells. The effect of MBZ on XIAP expression and induction of apoptotic pathways was evaluated by immunoblotting and co-immunoprecipitation techniques along with densitometric quantification. The growth inhibitory effects of MBZ were determined in a panel of melanoma cell lines with the sulphorhodamine (SRB) assay. siRNA techniques were used to reduce expression of XIAP. Results: Oral MBZ is as effective as the current standard of care temozolomide (TMZ) in reducing melanoma growth in vivo, with no notable toxicities observed. Inhibition of melanoma growth in vivo is accompanied by MBZ specific reduced expression of XIAP and cleavage of caspase 9. In response to MBZ treatment, sensitive cell lines display reduced levels of XIAP expression whereas resistant cell lines do not. Moreover, down-regulation of XIAP expression by siRNA in the MBZ-resistant melanoma cell line UACC1097 was accompanied by a reduction in the IC50 for MBZ from >10 μM to 3.7 μM. Exposure of melanoma cells to MBZ promotes the interaction of SMAC/DIABLO with XIAP, thereby alleviating inhibition of apoptosis by XIAP. Conclusions: In addition to demonstrating efficacy and safety in vivo, our preclinical studies of the promising anti-melanoma agent mebendazole provide insight into characterization of an apoptotic promoting mechanism of action. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4893. doi:1538-7445.AM2012-4893