Biological studies on Au(III) peptidomimetics about to enter Phase I clinical trials

Platinum-based drugs are well-established as effective antitumor agents, the progenitor being cisplatin.[1] However, since their therapeutic effectiveness is decreased due to some severe side-effects,[2] the design and development of alternative metal-based anticancer agents [3] are still a challenge. In this context, we have been studying gold(III)- dithiocarbamato derivatives of amino acids and oligopeptides with outstanding in vitro and in vivo activity along with negligible or no systemic toxicity.[4,5] Notably, these compounds showed no cross-resistance to cisplatin.[6] The most recent potential drugs were designed as carrier-mediated delivery systems exploiting peptide transporters, up-regulated in some cancer types. Among them, we focused our studies on two compounds which turned out to be very promising in preliminary screening tests on different human tumor cell lines.[7] Recently, we performed some tests on the triple-negative MDA-MB-231, highly metastatic, invasive and resistant to cisplatin, breast cancer cells. Our compounds showed interesting in vitro cytotoxic properties towards the aforementioned cancer cell line and in vivo on xenografts. Actually, an average 53% inhibition of tumor growth was recorded compared to control, after 27 days of treatment at 1.0 mg kg-1 d-1. Remarkably, some mice showed tumor shrinkage. With respect to their mechanism of action, we identified the proteasome as a major in vitro and in vivo target, thus suggesting a different mechanism of action compared to platinum-based drugs. Moreover, the treated mice did not show signs of weight loss, anorexia and/or fatigue. The acute toxicity studies, carried out on two groups of 40 mice, recognized the i.v. and per os well-tolerated doses in 15 mg/kg and 60 mg/kg, respectively. This class of compounds is expected to enter phase I clinical trials in a few months.