在一项新的研究中，来自美国耶鲁大学的研究人员发现目前正被用于治疗心力衰竭和房性心律失常（atrial arrhythmia）的几种药物也有望作为癌细胞的DNA破坏剂，也可能很容易改用为抗癌试剂。相关研究结果于2016年2月29日在线发表在Journal of the American Chemical Society期刊上，论文标题为“Characterization of Cardiac Glycoside Natural Products as Potent Inhibitors of DNA Double-Strand Break Repair by a Whole-Cell Double Immunofluorescence Assay”。

强心苷（cardiac glycosides）是在某些植物和昆虫中发现的具有生物活性的天然产物，有助心脏治疗，这是因为它们导致心脏收缩，从而增加心输出量。它们用于诸如洋地黄毒苷（Digitoxin）和毒毛旋花甙（Strophanthin）之类的处方药中。

如今，耶鲁大学研究人员也发现强心苷阻断肿瘤细胞中的DNA修复。由于肿瘤细胞快速分裂，它们的DNA更容易遭受损伤，因此抑制它们的DNA修复是一种大有希望的策略来选择性杀死这些细胞。已有科学家们注意到现强心苷具有抗癌效应，但是这些效应的科学依据还未很好地理解。在这项新的研究中，耶鲁大学研究人员证实强心苷抑制参与这种DNA修复的两种关键通路。

这项研究的研究结果提示着强心苷与磷酸化的DNA损伤关卡蛋白1调节剂（phospho-MDC1）或者E3泛素-蛋白连接酶环指蛋白8（ring finger protein 8, RNF8）相互作用，其中这两种蛋白因子都参与DNA双链断裂修复。

耶鲁大学医学院治疗性放射学助理教授Ranjit Bindra说，“我们与耶鲁大学分子发现中心一起进行高通量药物筛选，从中鉴定出一些令人关注的心脏药物也影响DNA修复。这为开发新的抗癌药物产生治疗上的影响。”

耶鲁大学化学教授Seth Herzon说，“我们的方法着重关注利用放射破坏癌细胞的DNA，然后测量在不同化合物存在下的DNA修复速率。总而言之，我们评估了2400种化合物。令人吃惊的是，我们认为强心苷抑制一种被称作53BP1的关键性DNA修复蛋白停留在DNA双链断裂位点上。这是一种非常令人关注的之前未曾预料到的活性。”

Herzon和Bindra说，同样的方法也能够被用来筛选几十万种化合物。他们的下一步就是改善强心苷的抗癌活性，同时调节它们的其他生物学影响。（来源：生物谷 Bioon.com）

Characterization of Cardiac Glycoside Natural Products as Potent Inhibitors of DNA Double-Strand Break Repair by a Whole-Cell Double Immunofluorescence Assay

Abstract  Small-molecule inhibitors of DNA repair pathways are being intensively investigated as primary and adjuvant chemotherapies. We report the discovery that cardiac glycosides, natural products in clinical use for the treatment of heart failure and atrial arrhythmia, are potent inhibitors of DNA double-strand break (DSB) repair. Our data suggest that cardiac glycosides interact with phosphorylated mediator of DNA damage checkpoint protein 1 (phospho-MDC1) or E3 ubiquitin–protein ligase ring finger protein 8 (RNF8), two factors involved in DSB repair, and inhibit the retention of p53 binding protein 1 (53BP1) at the site of DSBs. These observations provide an explanation for the anticancer activity of this class of compounds, which has remained poorly understood for decades, and provide guidance for their clinical applications. This discovery was enabled by the development of the first high-throughput unbiased cellular assay to identify new small-molecule inhibitors of DSB repair. Our assay is based on the fully automated, time-resolved quantification of phospho-SER139-H2AX (γH2AX) and 53BP1 foci, two factors involved in the DNA damage response network, in cells treated with small molecules and ionizing radiation (IR). This primary assay is supplemented by robust secondary assays that establish lead compound potencies and provide further insights into their mechanisms of action. Although the cardiac glycosides were identified in an evaluation of 2366 small molecules, the assay is envisioned to be adaptable to larger compound libraries. The assay is shown to be compatible with small-molecule DNA cleaving agents, such as bleomycin, neocarzinostatin chromophore, and lomaiviticin A, in place of IR.

原文链接：http://pubs.acs.org/doi/pdf/10.1021/jacs.6b00162