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Oxidative stress induced by Pt(IV) pro-drugs based on the cisplatin scaffold and indole carboxylic acids in axial position
Tolan, Dina; Gandin, Valentina; Morrison, Liam; El-Nahas, Ahmed; Marzano, Cristina; Montagner, Diego; Erxleben, Andrea
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, H-1 and Pt-195 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)(2)Cl-2(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. D.T. would like to thank the Egyptian Ministry of Higher Education (MoHE) for providing the financial support (PhD scholarship) for this research. This work was partially financially supported by the University of Padova (Grants 60A04-0443, 60A04-3189 and 60A04-4015/15).
Keyword(s): Platinum(IV) anticancer complexes; Ovarian cancer cells; Tetracarboxylatoplatinum(IV) complexes; Cyclooxygenase inhibitors; Indole-3-propionic acid; Indole-3-acetic acids; Lipid peroxidation; Cytotoxic activity; Icp-ms; Agents
Publication Date:
Type: Journal article
Peer-Reviewed: Yes
Language(s): English
Contributor(s): |~|
Institution: NUI Galway
Publisher(s): Nature Publishing Group
File Format(s): application/pdf
First Indexed: 2017-07-07 05:30:09 Last Updated: 2017-07-07 05:30:09