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

• Published in: Biochimica et biophysica acta. General subjects Vol. 1865; no. 10; p. 129963
• Main Authors: Mariani, D., Ghasemishahrestani, Z., Freitas, W., Pezzuto, P., Costa-da-Silva, A.C., Tanuri, A., Kanashiro, M.M., Fernandes, C., Horn, A., Pereira, M.D.
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.10.2021
• Subjects: antineoplastic activity; apoptosis; breast neoplasms; Cancer cells; cancer therapy; caspase-8; Cisplatin; copper; Copper(II) complex; Cytotoxicity; drug therapy; humans; lungs; mechanism of action; melanoma; membrane potential; mice; mitochondrial membrane; oxidation; Synergism; Xenograft; xenotransplantation; Copper(II) complex; Cytotoxicity; Xenograft; Synergism; Cisplatin; Cancer cells
• ISSN: 0304-4165; 1872-8006; 1872-8006
• DOI: 10.1016/j.bbagen.2021.129963

Intrinsic 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. In 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. We 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. The present study brings new clues regarding the mechanism of action of [Cu(HPClNOL)Cl]Cl, either alone or in combination with cisplatin. These results indicate that complex 1, administered either singly or in combination with current drugs, has real potential for use in cancer therapy.