title: Investigation of the cytotoxic implications of metal chelators against melanoma and approaches to improve the cytotoxicity profiles of metal coordinating agents.
abstract: 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.
authors.affiliation: School of Biomedical Sciences, Charles Sturt University, Orange, NSW, 2800, Australia.
authors.forename: Fady N
authors.initials: FN
authors.lastname: Akladios
authors.affiliation: School of Biomedical Sciences, Charles Sturt University, Orange, NSW, 2800, Australia.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Andrew
authors.affiliation: School of Biomedical Sciences, Charles Sturt University, Orange, NSW, 2800, Australia. cparkinson@csu.edu.au.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Parkinson
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002614:Chelating Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D003300:Copper / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D006834:Hydrazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D015394:Molecular Structure; D017382:Reactive Oxygen Species / Q000378:metabolism; D013329:Structure-Activity Relationship; D013882:Thiosemicarbazones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D002614:Chelating Agents; D056831:Coordination Complexes; D006834:Hydrazines; D017382:Reactive Oxygen Species; D013882:Thiosemicarbazones; C011368:thiocarbohydrazide; D003300:Copper
keywords: Cisplatin; Copper Thiosemicarbazone; Melanoma; Metal chelation; Metal transport; Reactive oxygen species (ROS)