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

IF 4.8 3区化学 Q1 CHEMISTRY, MEDICINAL

Natural Products and Bioprospecting Pub Date : 2023-08-29 DOI:10.1007/s13659-023-00392-1

Meichen Wang, Leilei Liang, Rong Wang, Shutao Jia, Chang Xu, Yuting Wang, Min Luo, Qiqi Lin, Min Yang, Hongyu Zhou, Dandan Liu, Chen Qing

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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.

Graphical abstract

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水仙素是一种新型的拓扑异构酶I抑制剂，具有很强的抗癌活性。

DNA拓扑异构酶是纠正DNA拓扑错误和维持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的先导化合物的丰富来源，包括抗肿瘤药物。在这项研究中，我们发现水仙素(NCS)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，逆转其对p-HOT DNA底物的解绕作用。但对topo II活性无明显影响。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topo I毒药。盲对接结果显示NCS可以与topo I结合，提示NCS可能是topo I抑制因子。此外，NCS在多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G2/M期，诱导细胞凋亡。我们的研究揭示了NCS的抗肿瘤机制，为开发基于topo I抑制的抗癌药物提供了良好的基础。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Natural Products and Bioprospecting CHEMISTRY, MEDICINAL-

CiteScore

8.30

自引率

2.10%

发文量

审稿时长

13 weeks

期刊介绍： Natural Products and Bioprospecting serves as an international forum for essential research on natural products and focuses on, but is not limited to, the following aspects: Natural products: isolation and structure elucidation Natural products: synthesis Biological evaluation of biologically active natural products Bioorganic and medicinal chemistry Biosynthesis and microbiological transformation Fermentation and plant tissue cultures Bioprospecting of natural products from natural resources All research articles published in this journal have undergone rigorous peer review. In addition to original research articles, Natural Products and Bioprospecting publishes reviews and short communications, aiming to rapidly disseminate the research results of timely interest, and comprehensive reviews of emerging topics in all the areas of natural products. It is also an open access journal, which provides free access to its articles to anyone, anywhere.