JBIC Journal of Biological Inorganic Chemistry ( IF 2.7 ) Pub Date : 2021-08-30 , DOI: 10.1007/s00775-021-01894-4 Jincan Chen 1, 2, 3 , Yuanyuan Deng 2 , Jie Wang 2 , Suxiang Chen 4 , Fa Peng 2 , Xuerong He 2 , Meijun Liu 2 , Hui Luo 1, 2, 3 , Jingjing Zhang 3, 5 , Lanmei Chen 1, 2
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Abstract
Two new cyclometalated Ru(II)-β-carboline complexes, [Ru(dmb)2(Cl-Ph-βC)](PF6) (dmb = 4,4′-dimethyl-2,2′-bipyridine; Cl-Ph-βC = Cl-phenyl-9H-pyrido[3,4-b]indole; RuβC-3) and [Ru(bpy)2(Cl-Ph-βC)](PF6) (bpy = 2,2′-bipyridine; RuβC-4) were synthesized and characterized. The Ru(II) complexes display high cytotoxicity against HeLa cells, the stabilized human cervical cancer cell, with IC50 values of 3.2 ± 0.4 μM (RuβC-3) and 4.1 ± 0.6 μM (RuβC-4), which were considerably lower than that of non-cyclometalated Ru(II)-β-carboline complex [Ru(bpy)2(1-Py-βC)] (PF6)2 (61.2 ± 3.9 μM) by 19- and 15-folds, respectively. The mechanism studies indicated that both Ru(II) complexes could significantly inhibit HeLa cell migration and invasion, and effectively induce G0/G1 cell cycle arrest. The new Ru(II) complexes could also trigger apoptosis through activating caspase-3 and poly (ADP-ribose) polymerase (PARP), increasing the Bax/Bcl-2 ratio, enhancing reactive oxygen species (ROS) generation, decreasing mitochondrial membrane potential (MMP), and inducing cytochrome c release from mitochondria. Further research revealed that RuβC-3 could deactivate the ERK/Akt signaling pathway thus inhibiting HeLa cell invasion and migration, and inducing apoptosis. In addition, RuβC-3-induced apoptosis in HeLa cells was closely associated with the increase of intracellular ROS levels, which may act as upstream factors to regulate ERK and Akt pathways. More importantly, RuβC-3 exhibited low toxicity on both normal BEAS-2B cells in vitro and zebrafish embryos in vivo. Consequently, the developed Ru(II) complexes have great potential on developing novel low-toxic anticancer drugs.
Graphic Abstract
中文翻译：
环金属化 Ru(II) β-咔啉配合物通过抑制 ERK 和 Akt 信号传导诱导人 HeLa 宫颈癌细胞的细胞周期停滞和凋亡
摘要
两个新的环金属化 Ru(II)-β-咔啉配合物，[Ru(dmb) 2 (Cl-Ph-βC)](PF 6 ) (dmb = 4,4'-dimethyl-2,2'-bipyridine; Cl- Ph-βC = Cl-苯基-9H-吡啶并[3,4-b]吲哚；RuβC-3 ) 和 [Ru(bpy) 2 (Cl-Ph-βC)](PF 6 ) (bpy = 2,2' -联吡啶；RuβC-4 ) 被合成和表征。Ru(II) 配合物对稳定的人宫颈癌细胞 HeLa 细胞具有高细胞毒性，IC 50值为 3.2 ± 0.4 μM ( RuβC-3 ) 和 4.1 ± 0.6 μM ( RuβC-4 )，显着低于非环金属化的Ru(II)-β-咔啉配合物[Ru(bpy) 2 (1-Py-βC)] (PF 6 )2 (61.2 ± 3.9 μM) 分别为 19 倍和 15 倍。机理研究表明，两种Ru(II)配合物均能显着抑制HeLa细胞的迁移和侵袭，有效诱导G0/G1细胞周期阻滞。新的 Ru(II) 复合物还可以通过激活 caspase-3 和聚 (ADP-核糖) 聚合酶 (PARP)、增加 Bax/Bcl-2 比率、增强活性氧 (ROS) 生成、降低线粒体膜电位来触发细胞凋亡(MMP)，并诱导线粒体释放细胞色素c 。进一步的研究表明，RuβC-3可以使ERK/Akt信号通路失活，从而抑制HeLa细胞的侵袭和迁移，诱导细胞凋亡。此外，RuβC-3诱导的 HeLa 细胞凋亡与细胞内 ROS 水平的升高密切相关，这可能是调节 ERK 和 Akt 通路的上游因子。更重要的是，RuβC-3对体外的正常 BEAS-2B 细胞和体内的斑马鱼胚胎均表现出低毒性。因此，所开发的Ru（II）配合物在开发新型低毒抗癌药物方面具有巨大潜力。
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