Phosphino copper(I) complexes as antitumor agents

Among non-Pt compounds, copper complexes are considered good alternatives to platinum drugs as antitumor agents [1]. Elevated levels of copper have been detected in various types of human cancer cells, and the altered copper metabolism of cancer cells as well as the differential response between normal and tumor cells to copper are the basis for the development of copper complexes endowed with antineoplastic characteristics. Recent studies have demonstrated that specific copper compounds are able to overcome classical drawbacks associated with Pt(II) drugs by virtue of a selective action toward tumor cells and the possibility to act against Pt-resistant tumor cells [2-5]. These features are consistent with the fact that copper complexes possess mechanism(s) of action different from platinum drugs. Among the variety of copper-based compounds synthesized so far for application in pharmaceutical studies endowing such properties, phosphine copper complexes represent an intriguing class. SARs revealed that structural modifications of phosphine copper(I) complexes through the modulation of ligand physicochemical characteristics as well as the stability/lability of the coordinative bonds lead to major changes in the biological activity, pharmacodynamic properties and cellular bioavailability. Recently, the monocationic copper(I) complex [Cu(thp)4][PF6] (CP) has been highlighted as a very promising agent [4]. The in vitro antitumor activity studies revealed a broad-spectrum and potent cytotoxicity against cancer cells derived from solid tumors, with IC50 values up to 15 and 35-fold lower than oxaliplatin and cisplatin, respectively. Interestingly, the selectivity index (SI) values were about 20- and 3-fold higher than those obtained with cisplatin and oxaliplatin, respectively. The characterization of CP-induced effects in cancer cells revealed the triggering of a non-apoptotic programmed cell death defined as paraptosis likely due to the inhibition of proteolytic activities of the 26S proteasome. By in vivo animal tests, the toxicity profile of CP has been explored after acute and repeated dose administrations. Studies on the antitumor efficacy of CP in models of solid tumor showed that CP was safe at a therapeutically effective dose, had a favorable pharmacokinetic profile and was effective against solid tumor models. The examination of CP biodistribution characteristics in tumor-bearing mice demonstrated that a significant and selective accumulation in the solid tumor mass was achieved [5].