title: Mixed copper-platinum complex formation could explain synergistic antiproliferative effect exhibited by binary mixtures of cisplatin and copper-1,10-phenanthroline compounds: An ESI-MS study.
abstract: Cisplatin, cis-diammineplatinum(II) dichloride, is a metal complex used in clinical practice for the treatment of cancer. Despite its great efficacy, it causes adverse reactions and most patients develop a resistance to cisplatin. To overcome these issues, a multi-drug therapy was introduced as a modern approach to exploit the drug synergy. A synergistic effect had been previously found when testing binary combinations of cisplatin and three copper complexes in vitro, namely, Cu(phen)(OH2)2(OClO3)2, [Cu(phen)2(OH2)](ClO4)2 and [Cu(phen)2(H2dit)](ClO4)2,(phen=1,10-phenanthroline, H2dit=imidazolidine-2-thione), against the human acute T-lymphoblastic leukaemia cell line (CCRF-CEM). In this work [Cu(phen)2(OH2)](ClO4)2 was also tested in combination with cisplatin against cisplatin-resistant sublines of CCRF-CEM (CCRF-CEM-res) and ovarian (A2780-res) cancer cell lines. The tested combinations show a synergistic effect against both the types of resistant cells. The possibility that this effect was caused by the formation of new adducts was considered and mass spectra of solutions containing cisplatin and one of the three copper complexes at a time were measured using electrospray ionisation at atmospheric-pressure mass spectrometry (ESI-MS). A mixed complex was detected and its stoichiometry was assessed on the basis of the isotopic pattern and the results of tandem mass spectrometry experiments. The formed complex was found to be [Cu(phen)(OH)μ-(Cl)2Pt(NH3)(H2O)](+).
authors.affiliation: Dipartimento di Scienze Chimiche e Geologiche, University of Cagliari, Cittadella Universitaria, 09042 Monserrato, Cagliari, Italy. Electronic address: tpivetta@unica.it.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Pivetta
authors.affiliation: Dipartimento di Scienze Chimiche e Geologiche, University of Cagliari, Cittadella Universitaria, 09042 Monserrato, Cagliari, Italy.
authors.forename: Viola
authors.initials: V
authors.lastname: Lallai
authors.affiliation: Dipartimento di Scienze Chimiche e Geologiche, University of Cagliari, Cittadella Universitaria, 09042 Monserrato, Cagliari, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Valletta
authors.affiliation: Dipartimento di Scienze Chimiche e Geologiche, University of Cagliari, Cittadella Universitaria, 09042 Monserrato, Cagliari, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Trudu
authors.affiliation: Dipartimento di Scienze Chimiche e Geologiche, University of Cagliari, Cittadella Universitaria, 09042 Monserrato, Cagliari, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Isaia
authors.affiliation: Dipartimento di Scienze Biomediche, University of Cagliari, Cittadella Universitaria, 09042 Monserrato, Cagliari, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Perra
authors.affiliation: Dipartimento di Scienze Biomediche, University of Cagliari, Cittadella Universitaria, 09042 Monserrato, Cagliari, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Pinna
authors.affiliation: Dipartimento di Scienze Biomediche, University of Cagliari, Cittadella Universitaria, 09042 Monserrato, Cagliari, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Pani
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000737:chemistry / Q000494:pharmacology*; D056831:Coordination Complexes / Q000737:chemistry / Q000494:pharmacology; D003300:Copper / Q000737:chemistry / Q000494:pharmacology*; D004357:Drug Synergism; D006801:Humans; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000737:chemistry*; D010618:Phenanthrolines / Q000737:chemistry*; D010984:Platinum / Q000737:chemistry*; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D009942:Organometallic Compounds; D010618:Phenanthrolines; C464760:copper-1,10-phenanthroline; D010984:Platinum; D003300:Copper; D002945:Cisplatin
keywords: Antiproliferative activity; Cisplatin; Cisplatin-resistant cells; Copper complexes; ESI–MS; Synergistic effect