A gallium(III)-polypyridyl complex bearing chrysin with anti-osteosarcoma stem cell activity

Case fatality rates associated with osteosarcoma increase sharply in patients with metastatic disease involving multiple sites. The tendency of osteosarcoma to metastasise has been linked to the presence of osteosarcoma stem cells (OSCs). Here, we report a gallium(III) complex (1) containing two 3,4,7,8-tetramethyl-1,10-phenanthroline ligands and chrysin, and investigate its in vitro anti-OSC activity. Complex 1 effectively eliminates OSCs grown in both two- and three-dimensional cultures at sub-micromolar to micromolar concentrations and is up to 130-fold more potent (based on half-maximal inhibitory concentration values) than the frontline anti-osteosarcoma metallodrug, cisplatin. Intracellular reactive oxygen species (ROS) studies suggest that the cytotoxic activity of 1 towards both bulk osteosarcoma cells and OSCs is mediated, at least in part, by intracellular ROS level elevation. Overall, this study highlights the promising anti-OSC potential of gallium(III)-based coordination complexes and represents the first report of an anti-OSC metal-flavonoid complex.