Wang Meichen, Liang Leilei, Wang Rong, Jia Shutao, Xu Chang, Wang Yuting, Luo Min, Lin Qiqi, Yang Min, Zhou Hongyu, Liu Dandan, Qing Chen
School of Pharmaceutical Science and Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, 1168 Western Chunrong Road, Yuhua Street, Cheng Gong District, Kunming, 650500, Yunnan, People's Republic of China.
Yunnan Infectious Disease Hospital, 28 km at Shi'an Road, Taiping Town, Anning, Kunming, 650301, Yunnan, China.
Nat Prod Bioprospect. 2023 Aug 29;13(1):27. doi: 10.1007/s13659-023-00392-1.
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 G/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.
DNA拓扑异构酶是校正拓扑DNA错误和维持DNA完整性所必需的核酶。拓扑异构酶抑制剂是一类具有明确疗效的重要癌症化疗药物。天然产物是药物发现中先导化合物的丰富来源，包括抗肿瘤药物。在本研究中，我们发现水仙环素（NCS），一种石蒜科生物碱，是一种新型的拓扑异构酶I（topo I）抑制剂。我们的数据表明，NCS抑制topo I活性并逆转其对p-HOT DNA底物的解旋作用。然而，它对topo II活性没有明显影响。NCS抑制topo I的分子机制表明，NCS在细胞中不稳定topo-DNA共价复合物，表明NCS不是一种topo I毒剂。一项盲对接结果表明，NCS可以与topo I结合，提示NCS可能是一种topo I抑制剂。此外，NCS在各种癌细胞中表现出强大的抗增殖作用。NCS将细胞周期阻滞在G/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抑制的抗癌药物开发提供了良好的基础。
