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An iridium (III) complex as potent anticancer agent induces apoptosis and autophagy in B16 cells through inhibition of the AKT/mTOR pathway
European Journal of Medicinal Chemistry ( IF 6.7 ) Pub Date : 2017-12-30 , DOI: 10.1016/j.ejmech.2017.12.087
Bing Tang , Dan Wan , Yang-Jie Wang , Qiao-Yan Yi , Bo-Hong Guo , Yun-Jun Liu

A new ligand THPDP (THPDP = 11-(6,7,8,9-tetrahydrophenazin-2-yl)dipyrido[3,2-a:2′,3′-c]phenazine) and its iridium(III) complex [Ir(ppy)2(THPDP)]PF6 (Ir-1) was synthesized and characterized by elemental analysis, IR, ESI-MS, 1H NMR and 13C NMR. The cytotoxicity in vitro of the complex against cancer cells B16, A549, Eca-109, SGC-7901, BEL-7402 and normal NIH 3T3 cell lines was evaluated using MTT method. The IC50 values of the complex toward B16, A549 and Eca-109 cells are 1.0 ± 0.02, 1.4 ± 0.03 and 1.6 ± 0.06 μM, respectively. The apoptosis was investigated with AO/EB and DAPI staining methods. The complex shows strong ability to inhibit the cell growth in B16, A549 and Eca-109 cells. Ir-1 can induce apoptosis, increase the intracellular ROS level, and cause a decrease in the mitochondrial membrane potential. The intracellular Ca2+ level and the release of cytochrome c were studied under a fluorescent microscope. The cell invasion and autophagy were also performed, and the cell cycle arrest was assayed by flow cytometry. The expression of Bcl-2 family proteins, PI3K, AKT, mTOR, P-mTOR was investigated by western blot. The results show that the complex induces apoptosis through ROS-mediated mitochondria dysfunction and inhibition of AKT/mTOR pathways. These findings are helpful for design and synthesis of iridium(III) complexes as potent anticancer drugs.



中文翻译:

铱(III)复合物作为有效的抗癌剂通过抑制AKT / mTOR途径诱导B16细胞凋亡和自噬

一种新的配体THPDP(THPDP = 11-(6,7,8,9-四氢吩嗪-2-基)二吡啶并[3,2- a:2',3'- c ]吩嗪)及其铱(III)络合物[合成并通过元素分析,IR,ESI-MS,1 H NMR和13 C NMR表征Ir(ppy)2(THPDP)] PF 6Ir-1)。使用MTT方法评估该复合物对癌细胞B16,A549,Eca-109,SGC-7901,BEL-7402和正常NIH 3T3细胞系的体外细胞毒性。IC 50朝向B16,A549和Eca-109细胞的复合物的值分别为1.0±0.02、1.4±0.03和1.6±0.06μM。用AO / EB和DAPI染色方法研究细胞凋亡。该复合物显示出强大的抑制B16,A549和Eca-109细胞生长的能力。Ir-1可以诱导细胞凋亡,增加细胞内ROS水平,并导致线粒体膜电位降低。细胞内Ca 2+在荧光显微镜下研究细胞色素c的水平和释放。还进行了细胞侵袭和自噬,并通过流式细胞术测定了细胞周期停滞。Western blot检测Bcl-2家族蛋白PI3K,AKT,mTOR,P-mTOR的表达。结果表明,该复合物通过ROS介导的线粒体功能障碍和抑制AKT / mTOR途径诱导细胞凋亡。这些发现有助于铱(III)配合物作为有效的抗癌药物的设计和合成。

更新日期:2017-12-30
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