Ruthenium arene complex induces cell cycle arrest and apoptosis through activation of P53-mediated signaling pathways

Abstract Ruthenium (Ru)-based complexes show promising prospect for development of anticancer agents. Among the cytotoxic Ru complexes, Ru arene complexes are famous for their comparatively high solubility in water under physiological conditions. However, more information is needed to understand the roles and effects of aquation reaction on the anticancer efficacy of these metal complexes. Herein, the aquation process of a Ru(II) arene complex [Ru(II) (C6H6) (3-MOIP)Cl]Cl (RuMOP) with potent anticancer activity was examined and characterized by UV–vis spectrometry, mass spectrometry, 1H NMR spectrometry and HPLC analysis. The results reveal that, aquation reaction occurred quickly in aqueous solution, with the chloride ligand replaced by hydrone. Moreover, the aquation process changed the complex's cellular uptake in tumour cells, finally affected its antiproliferative activity. The parent complex RuMOP could activate the caspase family proteins and p53 signaling pathways, showed high-level interaction with tumour cell membrane and death receptors. However, these cellular events and signaling could be blocked by aquation reaction. Taken together, these results help us to understand the anticancer action mechanisms of arene Ru complexes and provide important information for rational design of such kind of metal complexes with better cancer therapeutic potency.