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

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• 作者：Fady N. Akladios ; Scott D. Andrew ; Christopher J. Parkinson
• 关键词：Copper ; Zinc ; Cytotoxicity ; Reactive oxygen species (ROS) ; Thiosemicarbazone
• 刊名：Biometals
• 出版年：2016
• 出版时间：February 2016
• 年：2016
• 卷：29
• 期：1
• 页码：157-170
• 全文大小：3,084 KB
• 参考文献：Akladios FN, Andrew SD, Parkinson CJ (2015) Selective induction of oxidative stress in cancer cells via synergistic combinations of agents targeting redox homeostasis. Bioorgan Med Chem
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• 作者单位：Fady N. Akladios (1)
  Scott D. Andrew (1)
  Christopher J. Parkinson (1)
  
  1. School of Biomedical Sciences, Charles Sturt University, Orange, NSW, 2800, Australia
  
• 刊物类别：Biomedical and Life Sciences
• 刊物主题：Life Sciences
  Biochemistry
  Physical Chemistry
  
• 出版者：Springer Netherlands
• ISSN：1572-8773

文摘

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. Keywords Copper Zinc Cytotoxicity Reactive oxygen species (ROS) Thiosemicarbazone