title: Improved cytotoxicity of pyridyl-substituted thiosemicarbazones against MCF-7 when used as metal ionophores.
abstract: Zinc is the second most abundant transition metal in the human body, between 3 and 10% of human genes encoding for zinc binding proteins. We have investigated the interplay of reactive oxygen species and zinc homeostasis on the cytotoxicity of the thiosemicarbazone chelators against the MCF-7 cell line. The cytotoxicity of thiosemicarbazone chelators against MCF-7 can be improved through supplementation of ionic zinc provided the zinc ion is at a level exceeding the thiosemicarbazone concentration. Elimination of the entire cell population can be accomplished with this regime, unlike the plateau of cytotoxicity observed on thiosemicarbazone monotherapy. The cytotoxic effects of copper complexes of the thiosemicarbazone are not enhanced by zinc supplementation, displacement of copper from the complex being disfavoured. Treatment of MCF-7 with uncomplexed thiosemicarbazone initiates post G1 blockade alongside the induction of apoptosis, cell death being abrogated through subsequent supplementation with zinc ion after drug removal. This would implicate a metal depletion mechanism in the cytotoxic effect of the un-coordinated thiosemicarbazone. The metal complexes of the species, however, fail to initiate similar G1 blockade and apparently exert their cytotoxic effect through generation of reactive oxygen species, suggesting that multiple mechanisms of cytotoxicity can be associated with the thiosemicarbazones dependant on the level of metal ion association.
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 / Q000008:administration & dosage / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003300:Copper / Q000008:administration & dosage / Q000378:metabolism*; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D008958:Models, Molecular; D017382:Reactive Oxygen Species / Q000378:metabolism; D013329:Structure-Activity Relationship; D013882:Thiosemicarbazones / Q000008:administration & dosage* / Q000009:adverse effects; D015032:Zinc / Q000008:administration & dosage / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D013882:Thiosemicarbazones; D003300:Copper; D015032:Zinc
keywords: Copper; Cytotoxicity; Reactive oxygen species (ROS); Thiosemicarbazone; Zinc