Proteomics as a tool to disclose the cellular and molecular mechanisms of selected anticancer gold compounds

Abstract

• A panel of seven gold (I)/(III) compounds has been selected for proteomic studies. • The identified proteins by proteomics have been classified via Gene Ontology. • Three main modes of action highlighted: redox state, metabolism, protein synthesis. Gold compounds form an attractive class of cytotoxic metal compounds of potential application as anticancer agents. Notably, the mode of action of cytotoxic gold compounds appears to differ from that of the widely used anticancer Pt drugs -to which they were initially inspired- and to be basically DNA-independent. However, mechanistic details are still largely lacking for this class of metal-based drugs. To shed light on these issues we have developed a proteomic strategy that is capable of highlighting the perturbations in protein expression elicited by gold drugs in a selected cancer cell line with the final aim to disclose the underlying molecular mechanisms. In recent years, this type of strategy has been systematically applied, in our laboratory, to a representative panel of gold compounds including seven outstanding cytotoxic agents, i.e. six experimental gold(III) and gold(I) compounds and the clinical gold(I) drug, auranofin. A2780 human ovarian cancer cells were used as the standard cellular model for these studies. Proteins differentially expressed upon treatment were separated by 2-DE and identified by MALDI TOF and their meaning tentatively assessed through bioinformatic analysis. The occurrence of various and often overlapping molecular mechanisms was revealed. The affected proteins were found to belong -in most cases- to redox control systems and/or to the proteasome machinery implying that the severe cellular damage induced by gold compounds predominantly originates at these two distinct levels. However, for one Au(III) and one Au(I) compound, i.e. [(bipy dmb -H)Au(OH)][PF 6 ] (bipy dmb -H = deprotonated 6-(1,1-dimethylbenzyl)-2,2′-bipyridine) (Aubipyc) and the bis(1-butyl-3-methyl-imidazole-2-ylidene) gold(I) [Au(NHC) 2 ]PF 6 , a substantially greater number of proteomic alterations were detected pointing out, in both cases, to glucose metabolism as an additional target process of the cytotoxic action. The results that were obtained with the seven gold complexes are discussed in the frame of the available knowledge on anticancer gold drugs and their mechanisms. In general, our studies underscore the large amount of information that proteomic measurements may provide on the mode of action of metal-based drugs at the cellular level and delineate a very effective methodology for the identification of the respective cytotoxic mechanisms. We propose that the interpretation of the proteomic data in terms of the main affected cellular processes is further supported and validated through the implementation of complementary metabolomics and metallomics experiments.