Au(III)-Proline derivatives exhibiting selective antiproliferative activity against HepG2/SB3 apoptosis-resistant cancer cells

This paper deals with the combination of a proline-based moiety with biologically active gold centers in the oxidation states +1 and +3. In particular, six Au(i)/(iii)-proline dithiocarbamato (DTC) complexes with general formulae [AuI2(DTC)(2)] and [(AuX2)-X-III(DTC)] (X = Cl, Br) are reported here. After the synthesis of the ligand and the complexes, all derivatives were characterized via several techniques and tested for their stability in DMSO/water media. This study was focused on the demonstration of a peculiar behavior of Au(iii)-DTC species in solution. Finally, the complexes were screened for their antiproliferative activity against 2 human cancer cell lines, namely HepG2 and HepG2/SB3, taken as models of hepatocellular carcinoma. The latter, chosen for its aggressiveness due to the upregulation of the anti-apoptotic protein SerpinB3, was selectively inhibited in terms of growth by some Au(iii)-DTC complexes

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

Beyond platinums: gold complexes as anticancer agents

The accidental discovery of the anticancer properties of cisplatin in the mid 1960s has triggered the development of alternative platinum-based drugs. However, the platinum-based treatment of tumor diseases is massively hampered by severe side-effects and resistance development. Sulfurcontaining biomolecules play a significant role in platinum anticancer chemotherapy because of their high affinity to platinum(II) ion. Sulfur is involved in the entire metabolic process of platinum drugs. Strong and irreversible binding of cisplatin to intracellular thiolato ligands is considered as a major inactivation step, and reactions with sulfur donors in proteins are believed to affect enzymatic processes. Consequently, the development of novel metal-based compounds with a pharmacological profile different from that of the clinically-established platinum drugs is a major goal of modern medicinal chemistry and drug design. Among the non-platinum antitumor agents, gold(III) complexes have recently gained increasing attention due to their strong tumor cell growth inhibiting effects generally achieved by exploiting non-cisplatin-like mechanisms of action. The real breakthrough is not simply the use of gold compounds to treat cancer, but the rational design of gold-based drugs which may be very effective, non-toxic and potentially selective towards cancer cells, their potential impact relying on the possible site-specific delivery in localized cancers, thus strongly improving the cellular uptake and minimizing unwanted side-effects. Cancer cells are known to overexpress specific biomarkers and receptors needed for tumor growth. Among them, two integral plasma membrane proteins mediate the cellular uptake of di- and tripeptides and peptide-like drugs. They are present predominantly in epithelial cells of the small intestine, bile duct, mammary glands, lung, choroid plexus, and kidney but are also localized in other tissues and are upregulated in some types of tumors. Accordingly, we have been designing gold(III)- peptidedithiocarbamato derivatives which could combine both the antitumor properties and reduced side-effects of the previously reported gold(III) analogues1 with an enhanced bioavailability and tumor selectivity achieved by exploiting peptide transporters. Our compounds showed interesting in vitro cytotoxic properties towards a number of cancer cell lines and in vivo on xenograft models together with negligible organ and acute toxicity. With respect to their mechanism of action, we identified mitochondria and proteasome as major in vitro and in vivo targets. These results allowing the filing of an international patent2 for the use of gold(III) peptidomimetics in cancer chemotherapy as well as providing a solid starting point for them to enter Phase I clinical trials in a few month