Gold(III) compounds as anticancer agents: Relevance of gold-protein interactions for their mechanism of action.
Gold(III) compds. constitute an emerging class of biol. active substances, of special interest as potential anticancer agents. During the past decade a no. of structurally diverse gold(III) complexes were reported to be acceptably stable under physiol.-like conditions and to manifest very promising cytotoxic effects against selected human tumor cell lines, making them good candidates as anti-tumor drugs. Some representative examples will be described in detail. There is considerable interest in understanding the precise biochem. mechanisms of these novel cytotoxic agents. Based on exptl. evidence collected so far we hypothesize that these metallodrugs, at variance with classical platinum(II) drugs, produce in most cases their growth inhibition effects through a variety of "DNA-independent" mechanisms. Notably, strong inhibition of the selenoenzyme thioredoxin reductase and assocd. disregulation of mitochondrial functions were clearly documented in some selected cases, thus providing a solid biochem. basis for the pronounced proapoptotic effects. These observations led us to investigate in detail the reactions of gold(III) compds. with a few model proteins in order to gain mol.-level information on the possible interaction modes with possible protein targets. Valuable insight on the formation and the nature of gold-protein adducts was gained through ESI MS (electrospray ionization mass spectrometry) and spectrophotometric studies of appropriate model systems as it is exemplified here by the reactions of two representative gold(III) compds. with cytochrome c and ubiquitin. The mechanistic relevance of gold(III)-induced oxidative protein damage and of direct gold coordination to protein sidechains is specifically assessed. Perspectives for the future of this topics are briefly outlined.