Investigation of the cytotoxic implications of metal chelators against melanoma and approaches to improve the cytotoxicity profiles of metal coordinating agents
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The cytotoxic activity of thiosemicarbazones (TSC) and thiocarbohydrazones was investigated against the MelRm melanoma cell line. In general, the melanoma line was susceptible to metal coordinating agents, the most useful of which incorporated the dipyridyl ketone hydrazone sub-structure. The impact of copper supplementation on the cytotoxic activity towards the melanoma line (MelRm) of metal coordinating agents when acting as ionophores is less predictable than the general improvement that has been seen in other cancer cells such as breast adenocarcinoma (MCF-7). The bimetallic nature of thiocarbohydrazone complexes with resultant loss of lipophilicity is a limiting factor in usage against MelRm. The cytotoxic activity of TSC against MelRm when used as copper ionophores could be markedly improved through combination with a partner drug capable of disrupting cellular defences to oxidative stress. In the absence of copper supplementation, both TSC and thiocarbohydrazones could be used to initiate cell cycle arrest and this could be employed to improve cytotoxicity profiles of other metallodrugs such as cisplatin.
KeywordsCopper Thiosemicarbazone Metal chelation Metal transport Cisplatin Melanoma Reactive oxygen species (ROS)
F Akladios acknowledges the receipt of an Australian Postgraduate Award (APA). CJP wishes to thank the CSU Pharmacy Foundation for a grant partially funding this study. CJP and SDA thank the Kolling Institute (Royal North Shore Hospital) for the donation and characterization of the MelRm cell line employed in this study. We thank Dr N Proschogo (U Sydney) for the provision of mass spectrometry services and Professor D Richardson for discussions relating to the activation of copper and other metals.
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