From cisplatin to the design of original promising gold-based antineoplastic agents

Among the non-platinum anticancer agents, gold complexes have recently gained increasing attention due to their strong tumor cell growth inhibitory effects generally achieved by exploiting non-cisplatin-like pharmacodynamic and pharmacokinetic properties and mechanisms of action [1]. In this context, during the last decade, a number of gold(III)-dithiocarbamato derivatives have been designed and tested by our research group as potential anticancer agents, and up-to-date results have been recently reviewed [2,3]. The choice of dithiocarbamato ligands is not accidental; in fact, dithiocarbamates are still being evaluated for their efficacy as inhibitors of cisplatininduced nephrotoxicity without decreasing its antitumor activity. In particular, some compounds showed promising and outstanding properties in terms of greater in vitro and in vivo antitumor activity, reduced nephrotoxicity and acute toxicity compared to cisplatin [4]. The capability to overcome both acquired and intrinsic resistance showed by some types of tumors toward cisplatin confirms that they exert their antitumor activity by activating different apoptotic and non-apoptotic pathways compared to the clinically-established platinum-based drugs. Although their mechanism of action has not been completely elucidated yet, some potential biological targets have been identified, and proteasome has been recognized as a major in vitro and in vivo target [5], as well as the selenoenzyme thioredoxin reductase, both cytosolic and mitochondrial [6,7]. Thus, the idea of combining the antitumoral properties of metal ion with the presence of a dithiocarbamato moiety as intrinsic chemoprotectant, appears to be an original and innovative strategy in order to develop novel and more selective metal-based chemotherapeutic agents.