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

•Cisplatin and [Cu(phen)2(OH2)](ClO4)2 present synergistic effect vs. CCRF-CEM-res.•Cisplatin and [Cu(phen)2(OH2)](ClO4)2 present synergistic effect vs. A2780-res.•The mixed complex [Cu(phen)(OH)μ-(Cl)2Pt(NH3)(H2O)]+ was detected by ESI–MS study.•The ESI–MS appears as suitable tool for the study of the metal complexes formed in solution.

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)]+.

Graphical abstractBinary combinations of cisplatin and the copper complex [Cu(phen)2(OH2)](ClO4)2 present a synergistic antiproliferative effect against the cisplatin-resistant sublines of leukemic and ovarian cancer cells in vitro. A mixed complex containing copper and platinum with a stoichiometry of [Cu(phen)(OH)μ-(Cl)2Pt(NH3)(H2O)]+ was detected.Figure optionsDownload full-size imageDownload as PowerPoint slide