Tolan, Dina and Gandin, Valentina and Morrison, Liam and El-Nahas, Ahmed and Marzano, Cristina and Montagner, Diego and Erxleben, Andrea (2016) Oxidative Stress Induced by Pt(IV) Pro-drugs Based on the Cisplatin Scaffold and Indole Carboxylic Acids in Axial Position. Scientific Reports, 6 (29367). ISSN 2045-2322

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Abstract

The use of Pt(IV) complexes as pro-drugs that are activated by intracellular reduction is a widely investigated approach to overcome the limitations of Pt(II) anticancer agents. A series of ten mono- and bis-carboxylated Pt(IV) complexes with axial indole-3-acetic acid (IAA) and indole-3-propionic acid (IPA) ligands were synthesized and characterized by elemental analysis, ESI-MS, FT-IR, 1H and 195Pt NMR spectroscopy. Cellular uptake, DNA platination and cytotoxicity against a panel of human tumor cell lines were evaluated. All the complexes are able to overcome cisplatin-resistance and the most potent complex, cis,cis,trans-[Pt(NH3)2Cl2(IPA)(OH)] was on average three times more active than cisplatin. Mechanistic studies revealed that the trend in cytotoxicity of the Pt(IV) complexes is primarily consistent with their ability to accumulate into cancer cells and to increase intracellular basal reactive oxygen species levels, which in turn results in the loss of mitochondrial membrane potential and apoptosis induction. The role of the indole acid ligand as a redox modulator is discussed.

Item Type:	Article
Additional Information:	This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
Keywords:	Oxidative Stress; Pt(IV) complexes; Pro-drugs; Cisplatin Scaffold; Indole Carboxylic Acids;
Academic Unit:	Faculty of Science and Engineering > Chemistry
Item ID:	7815
Identification Number:	https://doi.org/10.1038/srep29367
Depositing User:	Diego Montagner
Date Deposited:	26 Jan 2017 16:47
Journal or Publication Title:	Scientific Reports
Publisher:	Nature Publishing Group
Refereed:	Yes
URI:	http://www.nature.com
Use Licence:	This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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