Cytotoxic effects of a mixed ligand copper(II) chelate complex against a panel of human and murine cancer cells in vitro. Theoretical study of the mechanism of biologic action through molecular modelling.

PURPOSE: In an effort to discover new compounds with anticancer activity, we have developed a novel copper (II) [Cu(II)] chelate complex with a tridentate ONNSchiff base ligand and the anion of salicylate and we evaluated the in vitro chemosensitivity of various human and murine tumor cell lines by measuring cell growth inhibition. The ultimate goal was to evaluate the existence of a potential antitumor activity of this complex. Beyond the cytotoxic activity assessment of the complex, we aimed at the elucidation of the underlying mechanism of action of this complex and its interactions with biological molecules, carrying out theoretical (quantum-chemical) calculations. MATERIALS AND METHODS: Cells grown in adherence or in suspension in 96-well microplates were exposed to Cu(II) complex for 24, 48 or 72 h. In vitro drug cytotoxicity was assessed by SRB and XTT colorimetric assays. Molecular modelling tools were used applying semiempirical and ab initio calculations. RESULTS: A series of experiments was carried out, showing a potent cytotoxic activity against most of the tested cancer cell lines. Quantum-chemical calculations demonstrate that the mechanism of the cellular damage can be explained, at least in part, by the ability of the nucleobases and nucleotides to be subject to nucleophilic attack on copper. CONCLUSION: Profound growth inhibitory effects were observed for the tested Cu(II) complex. It was also verified the hypothesis that the mechanism of action of this complex involves binding to DNA and RNA. These findings prompt to search for possible interaction of this complex with other cellular elements of fundamental importance for cell proliferation.