Expression profiling identifies epoxy anthraquinone derivative as a DNA topoisomerase inhibitor.
Expression profiling identifies epoxy anthraquinone derivative as a DNA topoisomerase inhibitor.
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DOI：
10.1016/j.canlet.2010.01.004
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发表时间：
2010-07-01
期刊：
影响因子：
9.7
通讯作者：
Khan J
中科院分区：
文献类型：
--
作者：
Gheeya J;Johansson P;Chen QR;Dexheimer T;Metaferia B;Song YK;Wei JS;He J;Pommier Y;Khan J
为了发现治疗神经母细胞瘤的新药，我们之前已经筛选了一组药物，并确定了30种针对神经母细胞瘤细胞的活性药物。在这里，我们进行了微阵列基因表达分析，以监测这些药物对神经母细胞瘤细胞系的影响，并使用连接图（cMAP）来探索未知药物的假定作用机制。我们首先比较了我们的数据集和cMAP数据库中共有的10种化合物的表达谱，并观察到10种匹配药物中有7种的高连接性得分，而不管所用细胞系的差异如何。未表征药物的cMAP筛选表明环氧蒽醌衍生物（EAD）的特征与多种已知DNA靶向剂（拓扑异构酶I/II抑制剂、DNA嵌入剂和DNA烷基化剂）的特征相匹配，如其结构所预测的。通过查询我们的内部NB-cMAP（http：//pob.abcc.ncifcrf.gov/cgi-bin/cMAP）（一个包含30种活性药物特征的数据库）获得了类似的结果。这些结果表明，环氧蒽醌衍生物可能通过靶向DNA复制抑制来抑制神经母细胞瘤细胞。实验数据还表明，环氧蒽醌衍生物确实通过DNA烷基化和抑制拓扑异构酶活性诱导DNA双链断裂。我们的研究表明，环氧蒽醌衍生物可能是一种新的DNA拓扑异构酶抑制剂，可用于治疗神经母细胞瘤或其他癌症患者。
To discover novel drugs for neuroblastoma treatment, we have previously screened a panel of drugs and identified 30 active agents against neuroblastoma cells. Here we performed microarray gene expression analysis to monitor the impact of these agents on a neuroblastoma cell line and used the connectivity map (cMAP) to explore putative mechanism of action of unknown drugs. We first compared the expression profiles of ten compounds shared in both our dataset and cMAP database and observed the high connectivity scores for 7 of 10 matched drugs regardless of the differences of cell lines utilized. The screen of cMAP for uncharacterized drugs indicated the signature of Epoxy anthraquinone derivative (EAD) matched the profiles of multiple known DNA targeted agents (topoisomerase I/II inhibitors, DNA intercalators, and DNA alkylation agents) as predicted by its structure. Similar result was obtained by querying against our internal NB-cMAP (http://pob.abcc.ncifcrf.gov/cgi-bin/cMAP), a database containing the profiles of 30 active drugs. These results suggest that Epoxy anthraquinone derivative may inhibit neuroblastoma cells by targeting DNA replication inhibition. Experimental data also demonstrate that Epoxy anthraquinone derivative indeed induces DNA double-strand breaks through DNA alkylation and inhibition of topoisomerase activity. Our study indicates that Epoxy anthraquinone derivative may be a novel DNA topoisomerase inhibitor that can be potentially used for treatment of neuroblastoma or other cancer patients.