Studies on the synergic activity of a three-drug cocktail active against cisplatin-resistant human leukemia and carcinoma cells

Objectives. At the light of properties and limits of cisplatin (CDDP) as an anticancer agent, and in view of the potential clinical relevance of the synergic effect of CDDP with the Cu(II)-phen complexes previously reported against T-leukemia cells (Pivetta et al.,Talanta, 2013), my research project was aimed at (1) extending the studies of CDDP-Cu(II)-phen combinations as such, as well as with the addition of a third drug component; (2) determining the potential degree of selectivity of the most synergic drug combinations. Methods. Most studies were focused on the most potent Cu(II)Phen compound (C0), lead of the cupper-phen complex series. Wild type and CDDP-resistant human T-leukemia CEM cells, wild type and CDDP-resistant human ovarian carcinoma A2780 cells, and ex vivo cultures of human peripheral blood lymphocytes from healthy donors, were used as cell models to characterize the cytotoxic activity of both binary and ternary drug combinations. Experimental Design (ED) and Artificial Neural Network (ANN) were used for setting experiments and for evaluation of data. Results. Binary and ternary drug combinations showed statistically significant synergisms either against the CDDP-sensitive and the CDDP-resistant cancer cell models. The three-drug cocktail was the most potent with a markedly higher cytotoxicity against leukemic lymphocytes than against ex vivo healthy proliferating lymphocytes. An ESI-MS study of CDDP-C0 mixed combination showed the formation of copper-platinum adducts which, leading to the release of a phenantroline moiety, may -at least in part- explain the synergism observed in the cell models. In addition, the analysis of phospholipid profiles showed lipid alterations in the CDDP-resistant CEM and A2780 cells with respect to their parental counterparts. Conclusions. Besides of the need of further studies to unveil the molecular target(s) of the triple-drug cocktail, based on the promising selectivity index (SI = 5) for cancer cells, investigations on its effectiveness in a xenograft mice models of human susceptible and CDDP-resistant ovarian carcinoma are on the way.