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首页> 外文期刊>Dalton transactions: An international journal of inorganic chemistry >Ruthenium complexes containing 2,6-bis(benzimidazolyl)pyridine derivatives induce cancer cell apoptosis by triggering DNA damage-mediated p53 phosphorylation
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Ruthenium complexes containing 2,6-bis(benzimidazolyl)pyridine derivatives induce cancer cell apoptosis by triggering DNA damage-mediated p53 phosphorylation

机译：包含2,6-双（苯并咪唑基）吡啶衍生物的钌配合物通过触发DNA损伤介导的p53磷酸化诱导癌细胞凋亡

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DNA has been identified as a primary target for anticancer drug design and remains one of the most promising biological receptors for the development of chemotherapeutic agents. We have previously demonstrated that ruthenium complex [Ru(bmbp)(phen)Cl]ClO _4 (RuBmP; bmbp = 2,6-bis(4-methylbenzimidazol-2- yl)pyridine) is a novel apoptosis-inducer by triggering mitochondria-mediated ROS overproduction in cancer cells. In the present work, the underlying mechanisms of the anticancer action of RuBmP were further elucidated by evaluating its DNA interaction properties and the regulating signalling pathways. Our results showed that RuBmP could effectively activate DNA strand breaks in A375 cells in a dose-dependent manner after cellular internalization. Phosphorylation of a DNA damage marker Histone H2A.X (Ser139) was thus up-regulated in treated cells. DNA damage subsequently activated p53 phosphorylation and inhibited the expression of Bcl-xL, resulting in activation of caspase-3, -8 and -9, and cleavage of poly(ADP-ribose) polymerase (PARP). The interactions between the complexes and cancer cell chromosomal and calf thymus DNA were characterized by UV-vis absorption, fluorescence intensity and viscosity measurements, which clearly demonstrated the intercalative binding of the complexes to DNA. Taken together, these results suggest that RuBmP, as a promising anticancer agent, induces cancer cell apoptosis by triggering DNA damage-mediated p53 phosphorylation.
机译：DNA已被确定为抗癌药物设计的主要目标，并且仍然是化学治疗药物开发中最有希望的生物受体之一。先前我们已经证明了钌络合物[Ru（bmbp）（phen）Cl] ClO _4（RuBmP; bmbp = 2,6-双（4-甲基苯并咪唑-2-基）吡啶）是一种新型的细胞凋亡诱导剂，通过触发线粒体-介导的ROS在癌细胞中的过度生产。在目前的工作中，RuBmP的抗癌作用的潜在机制通过评估其DNA相互作用特性和调节信号通路进一步阐明。我们的结果表明，RuBmP可以在细胞内化后以剂量依赖性方式有效激活A375细胞中的DNA链断裂。因此，DNA损伤标记组蛋白H2A.X（Ser139）的磷酸化在处理过的细胞中被上调。 DNA损伤随后激活了p53磷酸化并抑制了Bcl-xL的表达，导致caspase-3，-8和-9的激活，以及聚ADP-核糖聚合酶（PARP）的裂解。配合物与癌细胞染色体和小牛胸腺DNA之间的相互作用通过紫外可见吸收，荧光强度和粘度测量来表征，这清楚地证明了配合物与DNA的嵌入结合。综上，这些结果表明，RuBmP作为一种有前途的抗癌药，可通过触发DNA损伤介导的p53磷酸化来诱导癌细胞凋亡。

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