Narciclasine, a novel topoisomerase I inhibitor, exhibited potent anti-cancer activity against cancer cells

Natural Products and Bioprospecting

Original Article

Leilei Liang¹  Chang Xu²  Qiqi Lin²  Min Yang²  Dandan Liu²  Min Luo²  Rong Wang²  Shutao Jia²  Chen Qing²  Yuting Wang²  Hongyu Zhou²  Meichen Wang³ 

[1] Cell Biology and Molecular Biology Laboratory of Experimental Teaching Center, Faculty of Basic Medical Science, Kunming Medical University, 1168 Western Chunrong Road, Yuhua Street, Cheng Gong District, 650500, Kunming, Yunnan, China;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, 650500, Kunming, Yunnan, People’s Republic of China;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, 650500, Kunming, Yunnan, People’s Republic of China;Yunnan Infectious Disease Hospital, 28 km at Shi’an Road, Taiping Town, Anning, 650301, Kunming, Yunnan, China;

关键词: Topoisomerase;    Narciclasine (NCS);    Topo I-DNA covalent complex;    DNA damage;    Cell cycle;    Apoptosis;   

DOI  :  10.1007/s13659-023-00392-1

 received in 2023-06-10, accepted in 2023-08-21,  发布年份 2023

来源: Springer

【 摘 要 】

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

【 授权许可】

CC BY   
© Kunming Institute of Botany, CAS 2023

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