2016年3月15日訊 /生物谷BIOON/ --在一項新的研究中，來自美國耶魯大學的研究人員發現目前正被用於治療心力衰竭和房性心律失常（atrial arrhythmia）的幾種藥物也有望作為癌細胞的DNA破壞劑，也可能很容易改用為抗癌試劑。相關研究結果於2016年2月29日在線發表在Journal of the American Chemical Society期刊上，論文標題為「Characterization of Cardiac Glycoside Natural Products as Potent Inhibitors of DNA Double-Strand Break Repair by a Whole-Cell Double Immunofluorescence Assay」。
強心苷（cardiac glycosides）是在某些植物和昆蟲中發現的具有生物活性的天然產物，有助心臟治療，這是因為它們導致心臟收縮，從而增加心輸出量。它們用於諸如洋地黃毒苷（Digitoxin）和毒毛旋花甙（Strophanthin）之類的處方藥中。
如今，耶魯大學研究人員也發現強心苷阻斷腫瘤細胞中的DNA修復。由於腫瘤細胞快速分裂，它們的DNA更容易遭受損傷，因此抑制它們的DNA修復是一種大有希望的策略來選擇性殺死這些細胞。已有科學家們注意到現強心苷具有抗癌效應，但是這些效應的科學依據還未很好地理解。在這項新的研究中，耶魯大學研究人員證實強心苷抑制參與這種DNA修復的兩種關鍵通路。
這項研究的研究結果提示著強心苷與磷酸化的DNA損傷關卡蛋白1調節劑（phospho-MDC1）或者E3泛素-蛋白連接酶環指蛋白8（ring finger protein 8, RNF8）相互作用，其中這兩種蛋白因子都參與DNA雙鏈斷裂修復。
耶魯大學醫學院治療性放射學助理教授Ranjit Bindra說，「我們與耶魯大學分子發現中心一起進行高通量藥物篩選，從中鑑定出一些令人關注的心臟藥物也影響DNA修復。這為開發新的抗癌藥物產生治療上的影響。」
耶魯大學化學教授Seth Herzon說，「我們的方法著重關注利用放射破壞癌細胞的DNA，然後測量在不同化合物存在下的DNA修復速率。總而言之，我們評估了2400種化合物。令人吃驚的是，我們認為強心苷抑制一種被稱作53BP1的關鍵性DNA修復蛋白停留在DNA雙鏈斷裂位點上。這是一種非常令人關注的之前未曾預料到的活性。」
Herzon和Bindra說，同樣的方法也能夠被用來篩選幾十萬種化合物。他們的下一步就是改善強心苷的抗癌活性，同時調節它們的其他生物學影響。（生物谷Bioon.com）
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Characterization of Cardiac Glycoside Natural Products as Potent Inhibitors of DNA Double-Strand Break Repair by a Whole-Cell Double Immunofluorescence Assay
doi:10.1021/jacs.6b00162
Yulia V. Surovtseva†, Vikram Jairam‡, Ahmed F. Salem‡, Ranjini K. Sundaram‡, Ranjit S. Bindra*‡, and Seth B. Herzon
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.