Iridium (III) complexes induce cervical carcinoma apoptosis via disturbing cellular redox homeostasis disorder and inhibiting PI3K/AKT/mTOR pathway

Improvement of antineoplastic activity and selectivity is a main goal in the development of antineoplastic agents. Herein, we synthesized three new iridium (III) complexes: [Ir(ppy)(2)(FTTP)](PF6) (Ir1, ppy = 2-phenylpyridine, FTTP = 2-(3-fluoronaphthalen-2-yloxy)-1,4,8,9-tetraazatriphenylene), [Ir(bzq)(2)(FTTP)](PF6) (Ir-2, bzq = benzo [h]quinolone), [Ir(piq)(2)(FTTP)](PF6) (Ir-3, piq = 1-phenylisoquinoline). Ir1-3 exhibit excellent cytotoxicity against various cancer cells particularly towards human cervical carcinoma HeLa cells while remaining non-toxic to normal cell lines. Assays on 2D cell colony formation and 3D multicellular tumor spheroid model confirm that Ir1-3 can effectively inhibit the colony-forming and penetrate deeply into HeLa 3D multicellular tumor spheroid model exhibiting a notable cytotoxic effect, which was consistent with the results from the viability assays. Meanwhile, confocal microscopy shows a rapid uptake of Ir1-3 and co-localization experiments with subcellular markers reveal that Ir1-3 locate mainly at the mitochondria. Further investigation of the mechanism indicated the complexes Ir1-3 promote the excessive generation of ROS, inhibit glutathione and thioredoxin reductase that effectively interferes with the intracellular redox balance, induce oxidative stress and result in caspase-dependent apoptosis. Moreover, the ROS-mediated inactivation of the PI3K (phosphatidylinositol 3-kinase)/AKT (protein kinase B)/mTOR (mammalian target of rapamycin) pathway, DNA damage combing with suppression of the cyclin D1/CDK4/6 activity arrested cell cycle in the G0/G1 phase are involved in complexes-induced cell apoptosis. Finally, assays on xenografted cervical carcinoma mouse model confirm the excellent biocompatibility and antineoplastic efficiency of Ir3 in vivo. Collectively, this work offers building blocks for developing iridium (III) complexes as clinical application potential.

Automated summary

Three new iridium (III) complexes were synthesized and showed excellent cytotoxicity against various cancer cells, especially human cervical carcinoma HeLa cells. The complexes effectively inhibited cell colony formation and deep penetration into HeLa 3D multicellular tumor spheroids, resulting in notable cytotoxic effects. The rapid uptake of the complexes and their localization mainly at the mitochondria were observed through confocal microscopy. Mechanistic studies revealed that the complexes promoted excessive generation of reactive oxygen species (ROS), disrupted the intracellular redox balance, induced oxidative stress, and led to caspase-dependent apoptosis. In addition, the complexes induced cell apoptosis by inactivating the PI3K/AKT/mTOR pathway, causing DNA damage, and suppressing cyclin D1/CDK4/6 activity to arrest the cell cycle in the G0/G1 phase. The in vivo assays on a xenografted cervical carcinoma mouse model confirmed the excellent biocompatibility and antineoplastic efficiency of one of the complexes (Ir3). Overall, this work provides a foundation for the development of iridium (III) complexes with potential clinical applications.