Efficacy of Imidazole Antifungal Agents in the Treatment of Nras and Braf Mutant Human Melanoma Cells

Abstract

<b>Abstract ID 19624</b> <b>Poster Board 241</b> The incidence of melanoma, the most aggressive and lethal form of skin cancer, continues to rise each year in the United States. Current treatment options include conventional chemotherapy, immunotherapy, and targeted therapy. Disadvantages of these therapies, such as refractiveness and resistance, have contributed to poor outcomes in a significant number of melanoma patients. Therefore, there remains a need for new treatments. Imidazole antifungal agents potentially represent a class of new anticancer agents. Our objective here was to analyze the ability of various imidazole antifungal agents to exert anticancer effects in primary human metastatic melanoma cells, including those harboring well-known cancer mutations. The anticancer effects investigated were the induction of cell death via flow cytometry and decreased growth and proliferation via cell growth assay. Wild-type human melanoma cells, melanoma cells possessing the BRAF V600E mutation, and melanoma cells with the NRAS Q61R mutation were analyzed. The imidazole antifungal agents, clotrimazole, econazole, and miconazole, each induced significant increases in cell death and decreases in growth and proliferation in wild-type and Braf/Nras melanoma cells with doses of 10-50 μM. Of the antifungal agents utilized, overall clotrimazole resulted in the most efficacious effects. Interestingly, in Braf-mutant human melanoma cells, the antifungal agents led to profound decreases in cell growth but lesser effects on cell death. This may indicate an effect on cell cycle progression in Braf mutant cells. Taken together, these studies indicated that imidazole antifungal agents were effective in inducing antitumor effects in human metastatic melanoma cell lines, but with differing degrees of effects on cell death. This data suggests that melanoma tumors of each known genotype can potentially be treated with imidazole antifungal agents. In conclusion, this study demonstrated the ability of imidazole antifungal agents to induce anticancer effects in human metastatic melanoma cells, including those harboring well-known cancer mutations. Since differing levels of effects were observed using different antifungal agents, it is possible that each agent utilized affected different molecular targets in the melanoma cells. These antifungal agents thus appear to be potential alternative treatments, as well as affordable and widely accessible therapies, for melanoma patients in the future.