A research team identified Ru5 as a potent antitumor agent by screening a panel of ruthenium(II) polypyridine complexes containing β-carboline derivatives as ligands. By employing a photoaffinity tag and utilizing the photoaffinity-based protein profiling technology, the researchers successfully elucidated mitochondrial ATPase as the primary molecular target of Ru5. Their work is published in the journal National Science Review .
As an inhibitor of ATPase, Ru5 induces mitochondrial dysfunction , autophagy, and ferroptosis, which collectively contribute to its antitumor efficacy. Furthermore, comprehensive multi-omics analyses unveil the mechanism by which Ru5 activates the ferroptosis pathway via modulation of chloride channel protein expression, alternation in mitochondrial permeability, and elevation of reactive oxygen species levels. Additionally, Ru5 effectively suppresses the expression of epithelial-mesenchymal transition-related genes associated with cancer migration and invasion.
In vivo studies using a human lung cancer (A549) xenografted nude mouse model demonstrate superior tumor inhibition by Ru5 compared to the clinical drug cisplatin without causing significant weight loss or organ damage during treatment. This study not only offers novel insights into the mechanisms of action of ruthenium(II) polypyridine complexes in anticancer therapy but also presents innovative strategies for developing new metallo anticancer agents by integrating photoaffinity labeling te.