Novel Gold and Silver Carbene Complexes Exert Antitumor Effects Triggering the Reactive Oxygen Species Dependent Intrinsic Apoptotic Pathway

Cisplatin and other platinum-based drugs are well-known valid anticancer drugs. However, during the chemotherapy, the presence of numerous side effects and the onset of frequent phenomena of resistance pushes forward many research groups to devise new metal-based compounds holding improved anticancer properties and lower undesired effects. Amongst the variety of synthesized compounds, significant anti-proliferative effects were obtained employing organometallic compounds, particularly those based on silver or gold. With this in mind, we have synthesized four compounds, two silver- and two gold-complexes, with good inhibitory effects on the in vitro proliferation of breast and ovarian cancer cells models. The most active compound, i.e. AuL4, possess a 9-fold higher antitumor activity compared to cisplatin and induced dramatic morphological changes in HeLa cells. AuL4 induces PARP-1 cleavage, caspases 3/7 and 9 activation, mitochondria disruption, cytochrome c release in cancer cell cytoplasm and intracellular ROS production. Thus, AuL4 treatment causes cancer cells death by the intrinsic apoptotic pathway, whereas no cytotoxic effects were recorder treating non-tumoral cell lines. The reported outcomes may bring an important contribution to the expanding knowledge in medicinal bio-organometallic chemistry and enlarge the available anticancer toolbox, offering improved features, as a higher activity and/or selectivity, and opening the way to new discoveries and applications.