Ruthenium polypyridyl complexes as inducer of ROS-mediated apoptosis in cancer cells by targeting thioredoxin reductase
Ruthenium polypyridyl complexes as inducer of ROS-mediated apoptosis in cancer cells by targeting thioredoxin reductase
复制标题
钌聚吡啶复合物通过靶向硫氧还蛋白还原酶诱导癌细胞中ROS介导的细胞凋亡
DOI：
10.1039/c4mt00044g
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发表时间：
2014-01-01
期刊：
影响因子：
3.4
通讯作者：
Chen, Tianfeng
中科院分区：
文献类型：
--
作者：
Luo, Zuandi;Yu, Lianling;Chen, Tianfeng
TrxR是一种在许多癌症中上调的NADPH依赖性硒酶。它在癌症进展中起着关键作用，并成为抗癌药物越来越有吸引力的靶点。顺铂在癌症治疗中的局限性促使人们对其他金属配合物，尤其是钌（Ru）配合物进行广泛的研究。本论文对四种钌（Ⅱ）多吡啶二亚胺配合物[Ru（bpy）（3）]（2+）（1），[Ru（phen）（3）]（2+）（2），[Ru（ip）（3）]（2+）（3），[Ru（pip）（3）]（2+）（4）进行了体外生物活性评价（bpy = 2，2 ′-联吡啶，phen = 1，10-菲咯啉，ip =咪唑[4，5-f][1，10]菲咯啉，pip = 2-苯基咪唑[4，5-f][1，10]菲咯啉），并证明它们通过抑制TrxR而对A375人黑素瘤细胞显示抗增殖活性。随着结构平面性的增加，它们的TrxR抑制作用和体外抗癌活性增强。其中，配合物4表现出比顺铂更高的抗增殖活性，并且4的TrxR抑制效力比正TrxR抑制剂金诺芬更有效。复合物4通过诱导细胞凋亡抑制癌细胞生长，表现为亚G1期细胞群的积累、DNA断裂和核浓缩。此外，复合物4能够定位在线粒体中，并在其中通过抑制TrxR活性诱导ROS依赖性细胞凋亡。在暴露于复合物4的细胞中也触发了MAPK、AKT、DNA损伤介导的p53磷酸化和VEGFR信号传导的抑制的激活。在此基础上的证据，我们建议Ru多吡啶配合物可以开发为TrxR靶向剂，表现出应用潜力，用于治疗癌症。
TrxR is an NADPH-dependent selenoenzyme upregulated in a number of cancers. It plays a pivotal role in cancer progression and represents an increasingly attractive target for anticancer drugs. The limitations of cisplatin in cancer treatment have motivated the extensive investigation to other metal complexes, especially ruthenium (Ru) complexes. In this study, we present the in vitro biological evaluation of four Ru(II) polypridyl complexes with diimine ligands, namely, [Ru(bpy)(3)](2+) (1), [Ru(phen)(3)](2+) (2), [Ru(ip)(3)](2+) (3), [Ru(pip)(3)](2+) (4) (bpy = 2,2'-bipyridine, phen = 1,10-phenanthroline, ip = imidazole[4,5-f][1,10]phenanthroline, pip = 2-phenylimidazo[4,5-f][1,10]phenanthroline), and demonstrate that they exhibit antiproliferative activities against A375 human melanoma cells through inhibition of TrxR. As the planarity of the structure increases, their TrxR-inhibitory effects and in vitro anticancer activities were enhanced. Among them, complex 4 exhibited higher antiproliferative activity than cisplatin, and the TrxR-inhibitory potency of 4 was more effective than auranofin, a positive TrxR inhibitor. Complex 4 suppressed the cancer cell growth through induction of apoptosis as evidenced by accumulation of sub-G1 cell population, DNA fragmentation and nuclear condensation. Moreover, complex 4 was able to localize in mitochondria and therein induced ROS-dependent apoptosis by inhibition of TrxR activity. Activation of MAPKs, AKT, DNA damage-mediated p53 phosphorylation and inhibition of VEGFR signaling were also triggered in cells exposed to complex 4. On the basis of this evidence, we suggest that Ru polypyridyl complexes could be developed as TrxR-targeted agents that demonstrate application potentials for treatment of cancers.