Induction of Caspase-Mediated Apoptosis in Human Metastatic Melanoma Cells by Antifungal Agents

Abstract ID 129650 Poster Board 454 Melanoma remains as the most aggressive and lethal form of skin cancer for which new therapies are still needed. Current treatment options include conventional chemotherapy, immunotherapy, and targeted therapy. Disadvantages of these therapies, as well as other factors such as refractiveness, have contributed to poor outcomes in melanoma patients. Antifungal drugs potentially represent a novel class of anticancer agents that may lead to improved therapeutic outcomes for these patients. Our objective here was to analyze the ability of imidazole antifungal agents to selectively induce cell death in primary human metastatic melanoma cells, including those harboring well-known cancer mutations. The induction of cell death was analyzed by flow cytometry and immunoblotting detection of pro-cell death proteins. Wild-type human melanoma cell lines or those possessing the BRAF V600E mutation or the NRAS Q61R mutation were analyzed. All imidazole antifungal agent treatments (clotrimazole, econazole, and miconazole) led to significant increases in cell death in wild-type, BRAF, and NRAS mutant melanoma cells as revealed by flow cytometry. Positive immunoblot detection of activated caspase-9 and cleaved poly(ADP-ribose) polymerase-1 (PARP1) by Western blot in wild-type, BRAF, and NRAS mutant melanoma cells verified the induction of caspase-dependent cell death by the antifungal agent treatments. No significant cell death or detection of pro-cell death proteins was observed in normal skin cells and untreated melanoma cells. These results indicated that clotrimazole, econazole, and miconazole were effective in selectively inducing cell death in human metastatic melanoma cell lines while leaving normal skin cells unharmed. In conclusion, this study demonstrated the ability of antifungal agents to induce cell death, an important antitumor effect, in human metastatic melanoma cells. Not only was this cell death selectively induced in melanoma cells, but it also was induced in melanoma cells that harbor well-known driver mutations in cancer. This data provides additional evidence that imidazole antifungal agents potentially represent a novel class of drugs that can successfully treat melanoma.