School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, People's Republic of China.
Department of Pharmacy, Guangdong Second Provincial General Hospital, Guangzhou, 510317, People's Republic of China.
J Biol Inorg Chem. 2023 Jun;28(4):421-437. doi: 10.1007/s00775-023-01997-0. Epub 2023 Apr 25.
A new ligand DFIP (2-(dibenzo[b,d]furan-3-yl)-1H-imidazo[4,5-f][1,10]phenanthroline) and its two complexes iridium(III) Ir(ppy)(DFIP) (ppy = 2-phenylpyridine, Ir1) and ruthenium(II) Ru(bpy)(DFIP) (bpy = 2,2'-bipyridine, Ru1) were synthesized and characterized. The anticancer effects of the two complexes on A549, BEL-7402, HepG2, SGC-7901, HCT116 and normal LO2 cells were tested by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Complex Ir1 shows high cytotoxic activity on A549, BEL-7402, SGC-7901 and HepG2, Ru1 exhibits moderate anticancer activity toward A549, BEL-7402 and SGC-7901 cells. The IC values of Ir1 and Ru1 toward A549 are 7.2 ± 0.1 and 22.6 ± 1.4 μM, respectively. The localization of complexes Ir1 and Ru1 in the mitochondrial, intracellular accumulation of reactive oxygen species (ROS) levels, and the changes of mitochondrial membrane potential (MMP) and cytochrome c (cyto-c) were investigated. Apoptosis and cell cycle were detected by flow cytometry. Immunogenic cell death (ICD) was used to detect the effects of Ir1 and Ru1 on the A549 using a confocal laser scanning microscope. The expression of apoptosis-related proteins was detected by western blotting. Ir1 and Ru1 can increase the intracellular ROS levels and release cyto-c, reduce the MMP, leading to the apoptosis of A549 cells and blocking the A549 cells at the G0/G1 phase. Additionally, the complexes caused a decrease of the expression of polyADP-ribose polymerase (PARP), caspase 3, Bcl-2 (B-cell lymphoma-2), PI3K (phosphoinositide-3 kinase) and upregulated the expression of Bax. All these findings indicated that the complexes exert anticancer efficacy to induce cell death through immunogenic cell death, apoptosis, and autophagy.
一种新的配体 DFIP（2-(二苯并[b,d]呋喃-3-基)-1H-咪唑并[4,5-f][1,10]菲咯啉）及其两个配合物铱(III) Ir(ppy)(DFIP)（ppy=2-苯基吡啶，Ir1）和钌(II) Ru(bpy)(DFIP)（bpy=2,2'-联吡啶，Ru1）被合成并进行了表征。通过 3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑溴盐（MTT）法测试了两种配合物对 A549、BEL-7402、HepG2、SGC-7901、HCT116 和正常 LO2 细胞的抗癌作用。配合物 Ir1 对 A549、BEL-7402、SGC-7901 和 HepG2 具有高细胞毒性活性，Ru1 对 A549、BEL-7402 和 SGC-7901 细胞具有中等抗癌活性。Ir1 和 Ru1 对 A549 的 IC 值分别为 7.2±0.1 和 22.6±1.4 μM。研究了配合物 Ir1 和 Ru1 在线粒体中的定位、细胞内活性氧（ROS）水平的积累以及线粒体膜电位（MMP）和细胞色素 c（cyto-c）的变化。通过流式细胞术检测细胞凋亡和细胞周期。使用共聚焦激光扫描显微镜检测免疫原性细胞死亡（ICD）对 Ir1 和 Ru1 对 A549 的影响。通过蛋白质印迹法检测凋亡相关蛋白的表达。Ir1 和 Ru1 可以增加细胞内 ROS 水平并释放 cyto-c，降低 MMP，导致 A549 细胞凋亡并阻止 A549 细胞进入 G0/G1 期。此外，这些配合物还导致多聚 ADP-核糖聚合酶（PARP）、半胱天冬酶 3、Bcl-2（B 细胞淋巴瘤-2）、PI3K（磷酸肌醇-3 激酶）的表达下调，Bax 的表达上调。所有这些发现表明，这些配合物通过免疫原性细胞死亡、细胞凋亡和自噬发挥抗癌作用，诱导细胞死亡。
