Targeting the transposase domain of the DNA repair component Metnase to enhance chemotherapy.
Targeting the transposase domain of the DNA repair component Metnase to enhance chemotherapy.
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DOI：
10.1158/0008-5472.can-12-0313
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发表时间：
2012-12-01
期刊：
影响因子：
11.2
通讯作者：
Hromas R
中科院分区：
文献类型：
--
作者：
Williamson EA;Damiani L;Leitao A;Hu C;Hathaway H;Oprea T;Sklar L;Shaheen M;Bauman J;Wang W;Nickoloff JA;Lee SH;Hromas R
以前的研究表明，DNA修复成分Metnase(SETMAR)介导了对DNA损伤性癌症化疗的抵抗。Metnase有一个核酸酶结构域，与转座酶家族有相同的同源性。因此，我们几乎是根据550,000个化合物的ChemDiv文库来筛选三级Metnase结构，以确定可能对接在Metnase转座酶核酸酶区域的活性部位的小分子。我们确定了8个化合物为可能的Metnase抑制剂。有趣的是，这些候选抑制剂中有喹诺酮类抗生素和HIV整合酶抑制剂，它们具有共同的结构特征。以前的报道已经描述了喹诺酮类药物作为抗肿瘤药物的可能活性。因此，我们选择了喹诺酮类环丙沙星进行进一步的研究，因为它临床可用范围广，毒性低。我们发现环丙沙星抑制了Metnase切割DNA的能力，并抑制了Metnase依赖的DNA修复。环丙沙星本身不会引起DNA损伤，但它确实减少了化疗引起的DNA损伤的修复。环丙沙星增加了癌细胞系和异种移植瘤模型对临床相关化疗的敏感性。这些研究为先前推测的喹诺酮类药物的抗肿瘤活性提供了一种机制，并提示环丙沙星可能是一种简单而有效的癌症化疗辅助药物。
Previous studies have shown that the DNA repair component Metnase (SETMAR) mediates resistance to DNA damaging cancer chemotherapy. Metnase has a nuclease domain that shares homology with the Transposase family. We therefore virtually screened the tertiary Metnase structure against the 550,000 compound ChemDiv library to identify small molecules that might dock in the active site of the transposase nuclease domain of Metnase. We identified eight compounds as possible Metnase inhibitors. Interestingly, among these candidate inhibitors were quinolone antibiotics and HIV integrase inhibitors, which share common structural features. Previous reports have described possible activity of quinolones as antineoplastic agents. Therefore, we chose the quinolone ciprofloxacin for further study, based on its wide clinical availability and low toxicity. We found that ciprofloxacin inhibits the ability of Metnase to cleave DNA and inhibits Metnase-dependent DNA repair. Ciprofloxacin on its own did not induce DNA damage, but it did reduce repair of chemotherapy-induced DNA damage. Ciprofloxacin increased the sensitivity of cancer cell lines and a xenograft tumor model to clinically relevant chemotherapy. These studies provide a mechanism for the previously postulated antineoplastic activity of quinolones, and suggest that ciprofloxacin might be a simple yet effective adjunct to cancer chemotherapy.