Toxicogenetics evaluation and study of antiproliferative response mechanisms of ruthenium-based metallodrugs containing naphthoquinones ligands in tumor cells growing in conventional and 3D systems

Abstract

Recently, ruthenium complexes have occupied a prominent position in the search for new anti-cancer therapies due their potential of action, selectivity in tumor tissues and less toxicity compared to current platinum complexes in clinical use. The diversity of ligands has been shown to be crucial for these complexes reach multiple biological targets and thus overcome the limitation of current therapies. One approach for multi-target molecules is the combination of bioactive ligands with recognized antitumor properties, such as naphthoquinone derivatives. Thus, the aims of this study are based on the evaluation and characterization of toxicogenetics and antitumor properties of eight new ruthenium complexes containing the bioligands lapachol and lawsone. An initial screening will be performed by cell viability in prostate, lung, breast, colon and liver cancer. The complexes which show promising activity will be evaluated for their ability to interact to DNA by physico-chemical tests and the evaluation of genotoxicity in conventional and three-dimensional cell culture systems (3D). The possible mechanisms by which these complexes induce cell death will be evaluated on apoptosis and necrosis, generation of Reactive Oxygen Species (ROS) and expression of genes involved in key cellular growth pathways, epigenetics and drug metabolism. Finally, it is expected that the data achieved, allow to report any correlation between the structure and activity, in order to elucidate the possible mechanisms of action of these complexes. (AU)