Antitumoral synergism between a copper(II) complex and cisplatin improves in vitro and in vivo anticancer activity against melanoma, lung and breast cancer cells

Abstract

BackgroundIntrinsic resistance of cancer cells is a major concern for the success of chemotherapy, and this undesirable feature stimulates further research into the design of new compounds and/or alternative multiple drug chemotherapy protocols. MethodsIn this study, we investigated the antitumoral potential of the coordination compounds [Cu(HPClNOL)Cl]Cl (1), [Fe(HPClNOL)Cl2]NO3(2) and [Mn(HPClNOL)Cl2] (3). Using the human, MCF-7 and A549, and the murine melanoma, B16-F10, cell lines, we determined the cytotoxicity, DCFH oxidation, disruption of mitochondrial membrane potential (ΔΨm), Sub-G1 and TUNEL positive cells, and caspase 8 and 9 activities. Fractional inhibitory concentration (FIC) and xenograft models were also assessed to evaluate the efficacy of antitumoral potential. ResultsWe observed that only complex 1 was cytotoxic. The treatment of cancer cells with complex 1 triggered ROS generation and promoted the disruption of ΔΨm. Complex 1 increased the number of Sub-G1 and TUNEL positive cells, and the measurement of caspase 8 and 9 activity confirmed that apoptosis was triggered by the intrinsic pathway. FIC demonstrated that the combination of complex 1 with cisplatin was additive for the A549 cells whilst it was synergic for MCF-7 and B16-F10. Treatment with complex 1, either alone or combined with cisplatin, reduced tumor growth on xenograft models. ConclusionsThe present study brings new clues regarding the mechanism of action of [Cu(HPClNOL)Cl]Cl, either alone or in combination with cisplatin. General significanceThese results indicate that complex 1, administered either singly or in combination with current drugs, has real potential for use in cancer therapy.