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Narciclasine, a novel topoisomerase I inhibitor, exhibited potent anti-cancer activity against cancer cells |
| Meichen Wang1,3, Leilei Liang2, Rong Wang1, Shutao Jia1, Chang Xu1, Yuting Wang1, Min Luo1, Qiqi Lin1, Min Yang1, Hongyu Zhou1, Dandan Liu1, Chen Qing1 |
1. 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;
2. 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, Kunming, 650500, Yunnan, China;
3. Yunnan Infectious Disease Hospital, 28 km at Shi'an Road, Taiping Town, Anning, Kunming, 650301, Yunnan, China |
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Abstract 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.
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| Keywords
Topoisomerase
Narciclasine (NCS)
Topo I-DNA covalent complex
DNA damage
Cell cycle
Apoptosis
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| Fund:This work was supported by the National Natural Science Foundation of China (Grant Nos. 21907044, 81460559 and 82160697), Yunnan Fundamental Research Projects (Grant Nos. 202101AT070155 and 202201AS070086), Basic Research Plan of Yunnan Provincial Science and Technology Department-Kunming Medical University (Grant Nos. 202101AY070001-011, 202201AY070001-003 and 202101AY070001-041), the Ten Thousand Talent Plans for Young Top-notch Talents of Yunnan Province (Hongyu Zhou, Dandan Liu), Yunnan Academician Expert Workstation (Grant No. 202305AF150054). Basic Research Project of Yunnan Provincial Department of Education (Grant No. 2022J0213). |
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Corresponding Authors:
Hongyu Zhou,E-mail:zhouhongyu@kmmu.edu.cn;Dandan Liu,E-mail:liudandan1017@qq.com;Chen Qing,E-mail:qingchen@kmmu.edu.cn
E-mail: qingchen@kmmu.edu.cn;zhouhongyu@kmmu.edu.cn;liudandan1017@qq.com;qingchen@kmmu.edu.cn
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Issue Date: 08 October 2023
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