两个多吡啶钌(II)配合物[Ru(DIP)2(BIP)](PF6)2(DIP=4,7-二苯基-1,10-菲红,BIP=2-(1,1'-联苯-4-基)-1H-咪唑并[4,5-f][1,10]菲咯啉,Ru1)和[Ru(DIP)2(CBIP)](PF6)2(CBIP=2-(4'-氯-1,1'-联苯-4-基)-1H-咪唑并[4,5-f][1,10]菲咯啉,合成了Ru2)。Ru1,Ru2对B16,A549,HepG2,SGC-7901,HeLa,使用MTT方法(3-(4,5-二甲基噻唑)-2,5-二苯四唑溴化物)研究了BEL-7402,非癌症LO2。出乎意料的是,Ru1、Ru2不能阻止这些癌细胞的增殖。为了提高抗癌效果,我们用脂质体包裹Ru1,Ru2的复合物形成Ru1lipo,Ru2lipo.作为期望,Ru1lipo和Ru2lipo具有很高的抗癌功效,尤其是,Ru1lipo(IC503.4±0.1μM),Ru2lipo(IC503.5±0.1μM)在SGC-7901中显示出很强的阻断细胞增殖的能力。细胞集落,伤口愈合,和细胞周期分布表明,复合物可以有效地抑制G2/M期细胞的生长。用AnnexV/PI倍增法研究细胞凋亡,表明Ru1lipo和Ru2lipo可以有效诱导细胞凋亡。活性氧(ROS),丙二醛,谷胱甘肽和GPX4证明Ru1lipo和Ru2lipo改善ROS和丙二醛水平,抑制谷胱甘肽的产生,最终导致铁性死亡。Ru1lipo和Ru2lipo在溶酶体和线粒体上相互作用并损伤线粒体功能障碍。此外,Ru1lipo和Ru2lipo增加细胞内Ca2+浓度并诱导自噬。进行RNA序列和分子对接,Westernblot分析Bcl-2家族的表达。体内抗肿瘤实验证实,1.23mg/kg,2.46mg/kg的Ru1lipo具有53.53%和72.90%的高抑制率,可防止肿瘤生长,苏木素-伊红(H&E)结果显示,Ru1lipo不引起慢性器官损害,强烈促进实体瘤坏死。一起来看,我们得出结论,Ru1lipo和Ru2lipo通过以下途径引起细胞死亡:铁性凋亡,ROS调节的线粒体功能障碍,并阻断PI3K/AKT/mTOR。
Two polypyridyl ruthenium(II) complexes [Ru(DIP)2(BIP)](PF6)2 (DIP = 4,7-diphenyl-1,10-phenanthrolie, BIP = 2-(1,1\'-biphenyl-4-yl)-1H-imidazo[4,5-f][1,10]phenanthroline, Ru1) and [Ru(DIP)2(CBIP)](PF6)2 (CBIP = 2-(4\'-chloro-1,1\'-biphenyl-4-yl)-1H-imidazo[4,5-f][1,10]phenanthroline, Ru2) were synthesized. The cytotoxic activities in vitro of Ru1, Ru2 toward B16, A549, HepG2, SGC-7901, HeLa, BEL-7402, non-cancer LO2 were investigated using MTT method (3-(4,5-dimethylthiazole)-2,5-diphenltetraazolium bromide). Unexpectedly, Ru1, Ru2 can\'t prevent these cancer cells proliferation. To improve the anti-cancer effect, we used liposomes to entrap the complexes Ru1, Ru2 to form Ru1lipo, Ru2lipo. As expectation, Ru1lipo and Ru2lipo exhibit high anti-cancer efficacy, especially, Ru1lipo (IC50 3.4 ± 0.1 μM), Ru2lipo (IC50 3.5 ± 0.1 μM) display strong ability to block the cell proliferation in SGC-7901. The cell colony, wound healing, and cell cycle distribution show that the complexes can validly inhibit the cell growth at G2/M phase. Apoptotic studied with Annex V/PI doubling method showed that Ru1lipo and Ru2lipo can effectively induce apoptosis. Reactive oxygen species (ROS), malondialdehyde, glutathione and GPX4 demonstrate that Ru1lipo and Ru2lipo improve ROS and malondialdehyde levels, inhibit generation of glutathione, and finally result in a ferroptosis. Ru1lipo and Ru2lipo interact on the lysosomes and mitochondria and damage mitochondrial dysfunction. Additionally, Ru1lipo and Ru2lipo increase intracellular Ca2+ concentration and induce autophagy. The RNA-sequence and molecular docking were performed, the expression of Bcl-2 family was investigated by Western blot analysis. Antitumor in vivo experiments confirm that 1.23 mg/kg, 2.46 mg/kg of Ru1lipo possesses a high inhibitory rate of 53.53% and 72.90% to prevent tumor growth, hematoxylin-eosin (H&E) results show that Ru1lipo doesn\'t cause chronic organ damage and strongly promotes the necrosis of solid tumor. Taken together, we conclude that Ru1lipo and Ru2lipo cause cell death through the following pathways: autophagy, ferroptosis, ROS-regulated mitochondrial dysfunction, and blocking the PI3K/AKT/mTOR.