Mechanistic studies on cytotoxic gold compounds

Gold compounds form an attractive class of antiproliferative agents of potential use as anticancer agents. The molecular mechanisms through which gold compounds produce their biological effects are still largely unknown and the subject of intense investigations. Recent studies point out that the mechanism of action of cytotoxic gold compounds are essentially DNA-independent and cisplatin-unrelated, most likely relying on gold interactions with a few crucial proteins. Notably, various cellular proteins playing relevant functional roles were proposed to represent effective targets for cytotoxic gold compounds but these hypotheses still need validation [1]. Our research group has focused attention on the likely protein targets for cytotoxic gold compounds and on the elucidation of their molecular mechanisms. At present this goal is being pursued through two distinct approaches that will be described in detail. On one hand, studies are being carried out on isolated proteins; their interactions with representative gold compounds are studied through independent biophysical methods. Particularly informative is the joint use of X-ray diffraction and ESI MS on small model proteins that allowed us to define the actual molecular mechanisms of protein metalation [2]. On the other hand, studies are directed to monitor the alterations in the cell proteome caused by cancer cell exposure to cytotoxic gold compounds. This goal may be achieved through classical proteomic strategies. In a recent study we considered the effects of the gold(III) complex Aubipyc on A2780 ovarian cancer cells. From comparative analysis of 2D gels of treated versus control cancer cells it was possible to highlight a few protein spots that showed appreciable changes in their expression rates following drug exposure [3]. Subsequent bioinformatic analysis of these proteomic alterations provided valuable insight on the underlying biochemical processes ultimately leading to cell death.