Improved cytotoxicity of pyridyl-substituted thiosemicarbazones against MCF-7 when used as metal ionophores

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 speciesand zinc homeostasis on the cytotoxicityof the thiosemicarbazone chelators against the MCF-7cell line. The cytotoxicityof thiosemicarbazone chelators against MCF-7can 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 cytotoxicityobserved on thiosemicarbazone monotherapy. The cytotoxiceffects of copper complexes of the thiosemicarbazone are not enhanced by zinc supplementation, displacement of copper from the complex being disfavoured. Treatment of MCF-7with 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 cytotoxiceffect of the un-coordinated thiosemicarbazone. The metal complexes of the species, however, fail to initiate similar G1 blockade and apparently exert their cytotoxiceffect through generation of reactive oxygen species, suggesting that multiple mechanisms of cytotoxicitycan be associated with the thiosemicarbazones dependant on the level of metal ion association.