title: Oxidative Stress Induced by Pt(IV) Pro-drugs Based on the Cisplatin Scaffold and Indole Carboxylic Acids in Axial Position.
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, (1)H and (195)Pt 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.
authors.affiliation: School of Chemistry, National University of Ireland, Galway, Ireland.|Department of Chemistry, Faculty of Science, El-Menoufia University, Shebin El-Kom, Egypt.
authors.forename: Dina
authors.initials: D
authors.lastname: Tolan
authors.affiliation: Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Gandin
authors.affiliation: Earth and Ocean Sciences, School of Natural Sciences and Ryan Institute, National University of Ireland, Galway, Ireland.
authors.forename: Liam
authors.initials: L
authors.lastname: Morrison
authors.affiliation: Department of Chemistry, Faculty of Science, El-Menoufia University, Shebin El-Kom, Egypt.
authors.forename: Ahmed
authors.initials: A
authors.lastname: El-Nahas
authors.affiliation: Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Marzano
authors.affiliation: School of Chemistry, National University of Ireland, Galway, Ireland.|Department of Chemistry, National University of Ireland, Maynooth, Ireland.
authors.forename: Diego
authors.initials: D
authors.lastname: Montagner
authors.affiliation: School of Chemistry, National University of Ireland, Galway, Ireland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Erxleben
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D002264:Carboxylic Acids / Q000737:chemistry*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006706:Homeostasis; D006801:Humans; D007211:Indoles / Q000737:chemistry*; D008024:Ligands; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D011355:Prodrugs / Q000378:metabolism / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013057:Spectrum Analysis / Q000379:methods
chemical_list: D000970:Antineoplastic Agents; D002264:Carboxylic Acids; D007211:Indoles; D008024:Ligands; D011355:Prodrugs; D017382:Reactive Oxygen Species; D002945:Cisplatin