DNA topoisomerases are essential nuclear enzymes in correcting topological DNA errors and maintaining DNA integrity. Topoisomerase inhibitors are a significant class of cancer chemotherapeutics with a definite curative effect. Natural products are a rich source of lead compounds for drug discovery, including anti-tumor drugs. In this study, we found that narciclasine (NCS), an amaryllidaceae alkaloid, is a novel inhibitor of topoisomerase I (topo I). Our data demonstrated that NCS inhibited topo I activity and reversed its unwinding effect on p-HOT DNA substrate. However, it had no obvious effect on topo II activity. The molecular mechanism of NCS inhibited topo I showed that NCS did not stabilize topo-DNA covalent complexes in cells, indicating that NCS is not a topo I poison. A blind docking result showed that NCS could bind to topo I, suggesting that NCS might be a topo I suppressor. Additionally, NCS exhibited a potent anti-proliferation effect in various cancer cells. NCS arrested the cell cycle at G₂/M phase and induced cell apoptosis. Our study reveals the antitumor mechanisms of NCS and provides a good foundation for the development of anti-cancer drugs based on topo I inhibition.

Graphical abstract

中文翻译：

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Narciclasine 是一种新型拓扑异构酶 I 抑制剂，对癌细胞表现出有效的抗癌活性

DNA 拓扑异构酶是纠正拓扑 DNA 错误和维持 DNA 完整性的重要核酶。拓扑异构酶抑制剂是一类重要的癌症化疗药物，具有明确的疗效。天然产物是药物发现（包括抗肿瘤药物）先导化合物的丰富来源。在这项研究中，我们发现水仙环素 (NCS) 是一种石蒜科生物碱，是一种新型拓扑异构酶 I (topo I) 抑制剂。我们的数据表明，NCS 抑制拓扑 I 活性并逆转其对 p-HOT DNA 底物的解旋作用。但对topo II活性没有明显影响。NCS抑制拓扑I的分子机制表明，NCS不能稳定细胞内的拓扑-DNA共价复合物，表明NCS不是拓扑I毒物。盲对接结果显示NCS可以与topo I结合，表明NCS可能是topo I抑制剂。此外，NCS 在多种癌细胞中表现出有效的抗增殖作用。NCS将细胞周期阻滞在G ₂ /M期并诱导细胞凋亡。我们的研究揭示了NCS的抗肿瘤机制，为基于拓扑I抑制的抗癌药物的开发提供了良好的基础。

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