2D-DIGE analysis of ovarian cancer cell responses to cytotoxic gold compounds

Cytotoxic gold compounds hold today great promise as new pharmacological agents for treatment of human ovarian carcinoma; yet, their mode of action is still largely unknown. To shed light on the underlying molecular mechanisms, we performed 2D-DIGE analysis to identify differential protein expression in a cisplatin-sensitive human ovarian cancer cell line (A2780/S) following treatment with two representative gold(III) complexes that are known to be potent antiproliferative agents, namely AuL12 and Au2Phen. Software analysis using DeCyder was performed and few differentially expressed protein spots were visualized between the three examined settings after 24h exposure to the cytotoxic compounds, implying that cellular damage at least during the early phases of exposure is quite limited and selective reflecting the attempts of the cell to repair damage and to survive the insult. The potential of novel proteomic methods to disclose mechanistic details of cytotoxic metallodrugs is herein further highlighted. Different patterns of proteomic changes were highlighted for the two metallodrugs with only a few perturbed protein spots in common. Using MALDI-TOF MS and ESI-Ion trap MS/MS, several differentially expressed proteins were identified. Two of these were validated by western blotting: Ubiquilin-1, responsible for inhibiting degradation of protein such as p53 and NAP1L1, a candidate marker identified in primary tumors. In conclusion, we performed a comprehensive analysis of proteins regulated by AuL12 and Au2Phen, providing a useful insight into their mechanisms of action

Acridine-decorated cyclometallated gold(III) complexes: synthesis and anti-tumour investigations

(C^N) and (C^N^C) cyclometalated Au(III) represent a highly promising class of potential anticancer agents. We report here the synthesis of seven new cyclometalated Au(III) complexes with five of them bearing an acridine moiety attached via (N^O) or (N^N) chelates, acyclic amino carbenes (AAC) and N-heterocyclic carbenes (NHC). The antiproliferative properties of the different complexes were evaluated in vitro on a panel of cancer cells including leukaemia, lung and breast cancer cells. We observed a trend between the cytotoxicity and the intracellular gold uptake of some representative compounds of the series. Some of the acridine-decorated complexes were demonstrated to interact with ds-DNA using FRET-melting techniques

Gold complexes as antimicrobial agents

The antimicrobial properties of gold and its compounds are known since the late XIX century, following the discovery of the antitubercular activity of K[Au(CN)2] by Robert Koch. Further studies on gold complexes showed that their antimicrobial action is generally very fast, and the short exposure time required should avoid the development of some resistance among various sensitive bacteria and yeasts. Nowadays, resistance phenomena to available antibiotics represent a crucial issue in view of the lack of promptly available alternatives, and, in this framework, gold based compounds could be a convenient opportunity, as they may act on non-classical targets of microbial cells. Furthermore, reactivity, stability and toxicity of the metal centre can be easily tuned by the choice of the appropriate ligands. Most of the published papers concern the antimicrobial properties of AuI derivatives, while only a few reports on AuIII are present.[1] Interestingly, a recent example reports on the reproposal of the well-known antiarthritic drug Auranofin against some penicillin resistant Staphylococci. [2] In the light of these findings, a collection of gold complexes bearing polydentate heterocyclic nitrogen ligands has been assayed against a variety of Gram-negative/positive bacteria (Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, and Bacillus atrophaeus, Staphylococcus aureus, Streptococcus intermedius, respectively) and yeast (Candida albicans, Candida kruseii, Candida glabrata) with very promising results. The most of the tested compounds displayed severe inhibition of microbial cells proliferation during a short time of exposure. Analysis of their bacteriostatic/bactericidal action was carried out in vitro on both monolayer cultures and three-dimensional grown biofilms. Results of this study besides initial structure/activity correlations will be illustrated. References [1] Glišić, B. Đ.; Djuran, M. I. Dalton Transactions 2014, 43, 5950. doi:10.1039/c4dt00022f [2] Cassetta, M. I.; Marzo, T.; Fallani, S.; Novelli, A.; Messori, L. BioMetals 2014, 27, 787–791. doi:10.1007/s10534-014-9743-