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Increased generation of intracellular reactive oxygen species initiates selective cytotoxicity against the MCF-7 cell line resultant from redox active combination therapy using copper–thiosemicarbazone complexes

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Abstract

The combination of cytotoxic copper–thiosemicarbazone complexes with phenoxazines results in an up to 50-fold enhancement in the cytotoxic potential of the thiosemicarbazone against the MCF-7 human breast adenocarcinoma cell line over the effect attributable to drug additivity—allowing minimization of the more toxic copper–thiosemicarbazone component of the therapy. The combination of a benzophenoxazine with all classes of copper complex examined in this study proved more effective than combinations of the copper complexes with related isoelectronic azines. The combination approach results in rapid elevation of intracellular reactive oxygen levels followed by apoptotic cell death. Normal fibroblasts representative of non-cancerous cells (MRC-5) did not display a similar elevation of reactive oxygen levels when exposed to similar drug levels. The minimization of the copper–thiosemicarbazone component of the therapy results in an enhanced safety profile against normal fibroblasts.

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Acknowledgements

We wish to acknowledge the contribution of Dr Gregg Maynard for assistance in setting up flow cytometry studies. 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 MCF-7 cell line employed in this study and Dr N Proschogo (University of Sydney) for the provision of mass spectrometry expertise.

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Authors and Affiliations

  1. School of Biomedical Sciences, Charles Sturt University, Orange, NSW, 2800, Australia

    Fady N. Akladios, Scott D. Andrew & Christopher J. Parkinson

Authors
  1. Fady N. Akladios
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  2. Scott D. Andrew
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  3. Christopher J. Parkinson
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Correspondence to Christopher J. Parkinson.

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Akladios, F.N., Andrew, S.D. & Parkinson, C.J. Increased generation of intracellular reactive oxygen species initiates selective cytotoxicity against the MCF-7 cell line resultant from redox active combination therapy using copper–thiosemicarbazone complexes. J Biol Inorg Chem 21, 407–419 (2016). https://doi.org/10.1007/s00775-016-1350-2

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  • DOI: https://doi.org/10.1007/s00775-016-1350-2

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