[Cu(thp)4][PF6] as an Effective Therapeutic Agent for the Treatment of Solid Tumors, including Refractory Tumors

Among the variety of copper-based compounds synthetized so far for application in pharmaceutical studies, phosphine copper(I) compounds of ‘CuP4’ stoichiometry represent a class of promising candidates as antitumor agents.[1] The monocationic copper(I) complex [Cu(thp)4][PF6] (CP), highly soluble and stable in water solution, has been designed and investigated with the aim of discovering an alternative metallodrug to cisplatin (CDDP) showing advantage either in terms of overcoming of the drug resistance phenomenon and in terms of lower toxicity. The in vitro antitumor activity evaluation on a wide panel of human cancer cell lines (including the vast majority of human cancers of the NCI screening panel) revealed an impressive efficacy of CP, being up to 50-fold more cytotoxic than CDDP. Tested against a panel of colon carcinoma cell lines corresponding to different stages of disease progression and endowed with different degree of sensitivity to CDDP or oxaliplatin (OXP), CP elicited IC50 values up to 15 and 35-fold lower than OXP and CDDP, respectively. Interestingly, evaluating the cytotoxic activity of CP on human non-tumor cell lines, selectivity index (SI) values about 20- and 3-fold higher than those obtained with CDDP and OXP have been recorded. The characterization of CP-induced effects in cancer cells revealed the triggering of a non-apoptotic programmed cell death (PCD) defined as paraptosis (type III B cell death) likely due to the inhibition of proteolytic activities of 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 a model of solid tumor, the syngeneic murine Lewis lung carcinoma (LLC), showed that CP was safe at a therapeutically effective dose, it showed a favorable pharmacokinetic profile and it was therapeutically effective against the murine solid tumor model. The examination of CP biodistribution characteristics in tumor-bearing mice demonstrated that the copper drug achieved significant and selective accumulation in the solid tumor mass.