Ouabain, a cardiac glycoside, inhibits the Fanconi anemia/BRCA pathway activated by DNA interstrand cross-linking agents.
Ouabain, a cardiac glycoside, inhibits the Fanconi anemia/BRCA pathway activated by DNA interstrand cross-linking agents.
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DOI：
10.1371/journal.pone.0075905
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Lee CH
中科院分区：
文献类型：
--
作者：
Jun DW;Hwang M;Kim HJ;Hwang SK;Kim S;Lee CH
DNA修复途径的调节是开发抗癌药物的新兴靶点。DNA链间交联（ICL）是由顺铂和丝裂霉素C（MMC）等抗癌药物引起的最严重的DNA损伤形式之一，可激活范可尼贫血（FA）/BRCA DNA修复途径。抑制FA/BRCA通路可增强ICL诱导抗癌药物的细胞毒性作用，并可降低抗癌药物耐药性。为了寻找FA/BRCA通路抑制性小分子，我们建立了一种基于细胞的高含量筛选方法，通过测量DNA损伤上的FANCD 2灶来定量FA/BRCA通路的激活，然后将我们的方法应用于化学筛选。使用商业LOPAC 1280化学文库筛选，哇巴因被鉴定为有效的FA/BRCA途径抑制化合物。哇巴因是强心苷家族的成员，结合并抑制Na+/K+-ATP酶，多年来一直用于治疗心脏病。我们观察到哇巴因以及其他强心苷家族成员-洋地黄毒苷和地高辛-下调FANCD 2和FANCI mRNA水平，减少FANCD 2的单泛素化，抑制DNA损伤上FANCD 2灶的形成，并消除MMC处理诱导的细胞周期阻滞。哇巴因的这些抑制活性需要p38 MAPK，并且不依赖于细胞内Ca ~（2+）离子的增加或哇巴因的药物摄取抑制作用。此外，我们发现哇巴因增强MMC对肿瘤细胞的细胞毒作用。总之，我们确定了哇巴因作为FA/BRCA通路抑制化学增敏化合物的额外作用。这项研究的结果表明，哇巴因可能作为化疗增敏剂ICL诱导的抗癌药物。
Modulation of the DNA repair pathway is an emerging target for the development of anticancer drugs. DNA interstrand cross-links (ICLs), one of the most severe forms of DNA damage caused by anticancer drugs such as cisplatin and mitomycin C (MMC), activates the Fanconi anemia (FA)/BRCA DNA repair pathway. Inhibition of the FA/BRCA pathway can enhance the cytotoxic effects of ICL-inducing anticancer drugs and can reduce anticancer drug resistance. To find FA/BRCA pathway inhibitory small molecules, we established a cell-based high-content screening method for quantitating the activation of the FA/BRCA pathway by measuring FANCD2 foci on DNA lesions and then applied our method to chemical screening. Using commercial LOPAC1280 chemical library screening, ouabain was identified as a competent FA/BRCA pathway inhibitory compound. Ouabain, a member of the cardiac glycoside family, binds to and inhibits Na+/K+-ATPase and has been used to treat heart disease for many years. We observed that ouabain, as well as other cardiac glycoside family members―digitoxin and digoxin―down-regulated FANCD2 and FANCI mRNA levels, reduced monoubiquitination of FANCD2, inhibited FANCD2 foci formation on DNA lesions, and abrogated cell cycle arrest induced by MMC treatment. These inhibitory activities of ouabain required p38 MAPK and were independent of cellular Ca2+ ion increase or the drug uptake-inhibition effect of ouabain. Furthermore, we found that ouabain potentiated the cytotoxic effects of MMC in tumor cells. Taken together, we identified an additional effect of ouabain as a FA/BRCA pathway-inhibiting chemosensitization compound. The results of this study suggest that ouabain may serve as a chemosensitizer to ICL-inducing anticancer drugs.
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影响因子：
5.1
作者：
Felth, Jenny;Rickardson, Linda;Gullbo, Joachim
通讯作者：
Gullbo, Joachim
影响因子：
20.3
作者：
Chen, Q;Van der Sluis, PC;Dalton, WS
通讯作者：
Dalton, WS
影响因子：
15.9
作者：
Kennedy, Richard D.;Chen, Clark C.;D'Andrea, Alan D.
通讯作者：
D'Andrea, Alan D.
DOI：
10.1038/nrc3088
发表时间：
2011-06-24
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
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影响因子：
11.1
作者：
Aperia, A.
通讯作者：
Aperia, A.