Gallium(III)-2-benzoylpyridine-thiosemicarbazone complexes promote apoptosis through Ca2+ signaling and ROS-mediated mitochondrial pathways

摘要

Ga(iii) compounds are highly promising candidates for antitumor therapy. The level of intracellular reactive oxygen species (ROS) is significantly increased after Ga(iii) complex treatment, but these complexes are redox-inactive. To investigate the effects of Ga(iii) complexes on ROS levels, we synthesized three bis-ligated gallium(iii)-2-benzoylpyridine-thiosemicarbazone complexes and studied their antitumor mechanisms. The structures of the Ga(iii) complexes were identified by X-ray single-crystal diffraction. Cytotoxicity analysis demonstrated that the ligands and gallium complexes exerted a higher antitumor activity and a lower cytotoxicity than those of normal cells. The most active complex was C3, which exhibited a better antitumor viability than its related ligands and the anticancer agent 3-AP. Thus, the Ga(iii) complexes not only transmitted the iron ions but also induced intracellular Ca2+ release. As a result, the ROS standards in redox-active iron complexes were increased. The mechanism involved the release of Cyt C from the mitochondria which lack membrane potential, and then the activation of the caspase family proteins stimulated cell apoptosis.