Synergistic interactions of disulfiram, BSO and arsenic trioxide on drug resistant melanoma cell lines.

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Purpose: To investigate the cytotoxic effects of arsenic trioxide (ATO) in combination with disulfiram (DSF) and buthionine sulfoximine (BSO) on metastatic melanoma cells. Methods: Cell growth was measured using the XTT assay. Dose-response of multiple drugs was analyzed using Chou’s method for synergy analysis. Tietze’s enzymatic recycling method was used to determine cellular glutathione levels in drug-treated A375, M14, and c81-61 metastatic melanoma cells. Results: All three cell lines exhibited dose-dependent response to ATO, DSF, and BSO. The c81-61 cells were the least sensitive to the three agents tested. For A375 cells, the greatest synergy was observed for the combinations of 1.25uM ATO/0.25uM DSF, 1.25uM ATO/65.6uM BSO. For c81-61 cells, synergy was observed at 0.625uM ATO/0.125uM DSF and 0.3125uM ATO/15.625uM BSO. An enhanced anti-melanoma effect was observed for prolonged 6-day exposures. Total glutathione levels in ATO-treated A375 cells decreased from 48 hours to 72 hours. Conclusions: The synergistic cytotoxicity of ATO combination with DSF or BSO on A375, M14, and c81-61 cells may be associated with changes in intracellular glutathione (GSH) levels.