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

• Published in: Journal of inorganic biochemistry 2022-10, Vol.235, p.111946, Article 111946
• Main Authors: Hao, Jing, Liu, Haimei, Wang, Jiawen, Wang, Xiuzhen, Huang, Chunxia, Liang, Lijuan, Chen, Jing, Wang, Yi, Liu, Yunjun
• Format: Article
• Language: English
• Subjects: Animals; Anticancer activity in vivo; Antineoplastic Agents - pharmacology; Apoptosis; Carcinoma; Cell Line, Tumor; Cell Proliferation; Cervical carcinoma; Coordination Complexes - pharmacology; HeLa Cells; Homeostasis; Humans; Iridium (III) complexes; Iridium - pharmacology; Mice; Oxidative stress; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species - metabolism; ROS; TOR Serine-Threonine Kinases
• ISSN: 0162-0134; 1873-3344
• DOI: 10.1016/j.jinorgbio.2022.111946

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) (Ir2, bzq = benzo[h]quinolone), [Ir(piq)2(FTTP)](PF6) (Ir3, 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. Three new iridium(III) complexes were synthesized and characterized. The anticancer activity of the complexes was investigated. Complex [Ir(piq)2(FTTP)](PF6) (FTTP = 2-(3-fluoronaphthalen-2-yloxy)-1,4,8,9-tetraazatriphenylene, piq = 1-phenylisoquinoline) can effectively inhibit the tumor growth with an inhibitory rate of 54.8%. [Display omitted] •Three new iridium(III) complexes were synthesized and cytotoxicity in vitro and in vivo was studied.•Apoptosis, reactive oxygen species, colony formation, cell cycle arrest were studied.•The location and mitochondrial membra