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Novel Treatment of Human Melanoma Cells that Express BRAF or NRAS Mutations by Antifungal Agents
Author(s) -
Koh David W.,
Jira Lukas R.,
McKamey Shelby G.
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.09430
Subject(s) - neuroblastoma ras viral oncogene homolog , melanoma , econazole , clotrimazole , cancer research , mutant , wild type , programmed cell death , cell culture , biology , mutation , kras , apoptosis , gene , microbiology and biotechnology , genetics , antifungal , miconazole
Approximately 70% of all melanomas are characterized by mutations in the BRAF or NRAS genes. Although targeted therapy exists for BRAF mutations, this therapy is not commonly used in wild‐type melanoma, no such treatment is available for NRAS mutations, and resistance to all available treatments is increasing. These observations indicate that new strategies and targets are needed to improve melanoma therapy. We previously reported the potential for the antifungal agents, clotrimazole and econazole, to treat melanoma. Our objective here was to analyze the ability of these agents to treat human melanoma cell lines expressing the BRAF or NRAS mutations. Cell growth and cell death were investigated via flow cytometry, cell proliferation assays, and cell death assays after treatments. Wild‐type human melanoma cell lines or those possessing the BRAF V600E mutation or the NRAS Q61R mutation were analyzed. A dose of 25 μM clotrimazole led to profound decreases in cell growth in wild‐type and NRAS mutant melanoma cells. Significant, but lesser effects were observed in BRAF mutants. However, treatment with 25 μM econazole caused substantial reductions in cell growth in BRAF mutant cells, as well as one line of wild‐type melanoma cells. These results were corroborated by cell death analyses, where clotrimazole treatment caused up to 50% cell death in wild‐type and NRAS mutant cells after 3 days. In BRAF mutants after 3 days, econazole treatment caused up to 45% cell death. Taken together, these preliminary studies indicated that clotrimazole was more effective in the treatment of wild‐type and NRAS mutant melanoma cells, while econazole demonstrated greater effects in melanoma cells expressing the BRAF mutation. In conclusion, this study demonstrated the ability of antifungal agents to successfully treat human melanoma cell lines that possess BRAF and NRAS mutations. Since each agent displayed differential effects for each type of mutation, it is possible that these antifungal agents affect different molecular targets in each mutant melanoma cell line. These antifungal agents thus appear to be potential alternative treatments for wild‐type melanoma or melanoma characterized with the BRAF V600E or NRAS Q61R mutation.