Induction of apoptosis in SGC-7901 cells by iridium(III) complexes via endoplasmic reticulum stress-mitochondrial dysfunction pathway

This study was intended to evaluate the anticancer activity of three newly synthesized iridium(III) complexes [Ir(ppy) 2 (PEIP)](PF 6 ) ( 1 ) (ppy = 2-phenylpyridine, PEIP = 2-phenethyl-1 H -imidazo[4,5-f][1,10]phenanthroline), [Ir(ppy) 2 (SIP)](PF 6 ) ( 2 ) (SIP = (E)-2-styryl-1 H -imidazo[4,5-f][1,10]phenanthroline) and [Ir(ppy) 2 (PEYIP)](PF 6 ) ( 3 ) (PEYIP = 2-phenethynyl-1 H -imidazo[4,5-f][1,10]phenanthroline). The cytotoxic activity in vitro against A549, SGC-7901, HepG2, HeLa and normal NIH3T3 cells was investigated by 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) method. We found that the complexes 1 , 2 and 3 significantly inhibited cell proliferation, in particular, complexes 2 and 3 show high cytotoxic effect on SGC-7901 cells with an IC 50 value of 5.8 ± 0.7 and 4.4 ± 0.1 μM. Moreover, cell cycle assay revealed that the complexes could block G2/M phase of the cell cycle. Apoptotic evaluation by Annexin V/PI staining indicated that complexes 1 – 3 can induce apoptosis in SGC-7901 cells. In addition, microscopy detection suggested that disruption of mitochondrial functions, characterized by increased generation of intracellular ROS and Ca 2+ as well as decrease of mitochondrial membrane potential. Western blot analysis shows that the complexes upregulate the expression of pro-apoptotic Bax and downregulate the expression of anti-apoptotic Bcl-2, which further activates caspase-3 and prompts the cleavage of PARP. Taken together, these results demonstrated that complexes 1 – 3 exert a potent anticancer effect on SGC-7901 cells via ROS-mediated endoplasmic reticulum stress-mitochondrial apoptotic pathway and have a potential to be developed as novel chemotherapeutic agents for human gastric cancer. Graphical abstract Three new iridium(III) complexes [Ir(ppy) 2 (PEIP)](PF 6 ) ( 1 ) (ppy = 2-phenylpyridine, PEIP = 2-phenethyl-1 H -imidazo[4,5-f][1,10]phenanthroline), [Ir(ppy) 2 (SIP)](PF 6 ) ( 2 ) (SIP = 2-styryl-1 H -imidazo[4,5-f][1,10]phenanthroline) and [Ir(ppy) 2 (PEYIP)](PF 6 ) ( 3 ) (PEYIP = 2-phenethynyl-1 H -imidazo[4,5-f][1,10]phenanthroline) were synthesized and characterized. The anticancer activity in vitro was investigated by 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) method. The results show that the complexes induce apoptosis via ROS-mediated endoplasmic reticulum stress-mitochondrial dysfunction pathway.