A new strategy in chemotherapy: preliminary studies on Cu(II) complexes aimed at exploiting the enhanced copper uptake in malignancies

Copper is an essential trace element for living organisms and, in particular, is the third most abundant transition metal ion in human body. Due to its easy switching from Cu(I) to Cu(II) under physiological conditions, copper is found in many metalloproteins and enzymes in the form of Cu(I), Cu(II) and also Cu(III) ions. Concerning the relationship between copper and cancer, in 1980s, it was proposed that copper plays an important role in angiogenesis. In particular, it was found that three copperbinding proteins (ceruloplasmin, heparin, and glycyl-L-histidyl-L-lysine) are essential factors to generate new blood vessels from the existing vascular bed. Interestingly, among the transition metals, only copper was found to stimulate the secretion of several angiogenic mediators such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and interleukin-1 (IL-1).[1] Moreover, the abnormal accumulation of copper in cancer cells seems to be a distinguishing characteristic between transformed and healthy cells. This finding encouraged the development of several copper complexes able to take advantage of such atypical metabolic requirement. Their ability to kill tumor cells is mainly related to the induction of an oxidative stress that leads to cell death either by necrosis or through the activation of the apoptotic process.[2,3] Based on these considerations, in the past we designed some copper(II)-complexes with sulfur-donor ligands that proved to be very potent toward a wide panel of human tumor cell lines.[4,5] Here we present the synthesis and the physico-chemical characterization of some copper dithiocarbamato complexes and we compare the different classes of such compounds in their chemical and biological properties. Three different types of dithiocarbamato compounds derived from primary amines, amines containing heteroatoms and methylated ones, have been investigated. The in vitro antiproliferative evaluation highlighted that some of them are able to induce cell death in human cervix adenocarcinoma cells (HeLa cell line) with IC50 values comparable or lower than that obtained for cisplatin.