title: Cytotoxicity in human cancer cells and mitochondrial dysfunction induced by a series of new copper(I) complexes containing tris(2-cyanoethyl)phosphines.
abstract: Over the last few years a lot of research has been done to develop novel metal-based anti-cancer drugs, with the aim of improving clinical effectiveness, reducing general toxicity, and broadening the spectrum of activity. The search for novel metal-based antitumour drugs other than Pt agents includes the investigation of the cytotoxic activity of copper(I/II) compounds. Among these copper agents, particular attention has been recently devoted to hydrophilic copper(I) species bearing phosphines because of their noteworthy stability in aqueous media together with their remarkable in vitro cytotoxic activity. In this study we report on the synthesis, characterization and cytotoxic assays of a series of Cu(I) complexes with tris(2-cyanoethyl)phosphine (PCN) and bis(2-cyanoethyl)phenylphosphine (PCNPh). They were prepared by reaction of [Cu(CH(3)CN)(4)](+) or CuX(2) precursors with the pertinent phosphine in acetone or acetonitrile solutions producing compounds of the following formulation: [Cu(PCN)(2)](+) 2, [Cu(CH(3)CN)(PCN)](+) 3, [Cu(X)(PCN)] (X = Cl, 4; Br, 5), and [Cu(PCNPh)(2)](+) 6. The new copper(I) complexes were tested for their cytotoxic properties against a panel of several human tumour cell lines. Cellular copper uptake rate was correlated with cell growth inhibition in 2008 human ovarian cancer cells. Moreover, copper(I)-PCN complexes were evaluated for their ability to alter the most relevant mitochondrial pathophysiological parameters such as respiration, coupling, ATP-synthetase activity and membrane potential in isolated mitochondria. These data were correlated with changes in mitochondrial membrane potential and production of reactive oxygen species (ROS) in drug-treated 2008 cells.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Padova, via Marzolo 5, 35131, Padova, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Zanella
authors.forename: Valentina
authors.initials: V
authors.lastname: Gandin
authors.forename: Marina
authors.initials: M
authors.lastname: Porchia
authors.forename: Fiorenzo
authors.initials: F
authors.lastname: Refosco
authors.forename: Francesco
authors.initials: F
authors.lastname: Tisato
authors.forename: Francesca
authors.initials: F
authors.lastname: Sorrentino
authors.forename: Guido
authors.initials: G
authors.lastname: Scutari
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Rigobello
authors.forename: Cristina
authors.initials: C
authors.lastname: Marzano
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003300:Copper / Q000737:chemistry*; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000473:pathology; D010720:Phosphines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D010720:Phosphines; D017382:Reactive Oxygen Species; D003300:Copper