DNA拓扑异构酶是纠正拓扑DNA错误和维持DNA完整性的必需核酶。拓扑异构酶抑制剂是一类具有明确治疗效果的肿瘤化疗药物。天然产物是药物发现中富含铅化合物的丰富来源，包括抗肿瘤药物。在本研究中，我们发现Narciclasine（NCS），一种石蒜科生物碱，是拓扑异构酶I（topo I）的一种新型抑制剂。我们的数据表明，NCS抑制了topo I的活性，并逆转了其对p-HOT DNA底物的解旋效应。然而，它对topo II的活性没有明显影响。NCS抑制topo I的分子机制表明，NCS不稳定细胞中的topo-DNA共价复合物，表明NCS不是一种topo I毒药。盲对接结果显示NCS能与topo I结合，暗示NCS可能是一种topo I抑制剂。此外，NCS在各种癌细胞中展示出强效的抗增殖效应。NCS将细胞周期阻滞在G2/M期，并诱导细胞凋亡。我们的研究揭示了NCS的抗肿瘤机制，并为基于topo I抑制开发抗癌药物奠定良好的基础。© 2023. 中国科学院昆明植物研究所。

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.© 2023. Kunming Institute of Botany, CAS.