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

doi:10.1007/s13659-023-00392-1

Natural Products and Bioprospecting ›› 2023, Vol. 13 ›› Issue (4): 27-27.DOI: 10.1007/s13659-023-00392-1

• ORIGINAL ARTICLES • Previous Articles Next Articles

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

Meichen Wang^1,3, 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

Received:2023-06-10 Online:2023-10-08 Published:2023-08-24
Contact: Hongyu Zhou,E-mail:zhouhongyu@kmmu.edu.cn;Dandan Liu,E-mail:liudandan1017@qq.com;Chen Qing,E-mail:qingchen@kmmu.edu.cn
Supported by:
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).

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

Meichen Wang^1,3, 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

通讯作者: Hongyu Zhou,E-mail:zhouhongyu@kmmu.edu.cn;Dandan Liu,E-mail:liudandan1017@qq.com;Chen Qing,E-mail:qingchen@kmmu.edu.cn
基金资助:
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).

Abstract

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.

Key words: Topoisomerase, Narciclasine (NCS), Topo I-DNA covalent complex, DNA damage, Cell cycle, Apoptosis

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.

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

Meichen Wang, Leilei Liang, Rong Wang, Shutao Jia, Chang Xu, Yuting Wang, Min Luo, Qiqi Lin, Min Yang, Hongyu Zhou, Dandan Liu, Chen Qing. Narciclasine, a novel topoisomerase I inhibitor, exhibited potent anti-cancer activity against cancer cells[J]. Natural Products and Bioprospecting, 2023, 13(4): 27-27.

References

1. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics. CA Cancer J Clin. 2021;71:7–33.
2. Patil VM, Masand N. Natural product databases and tools for anti-cancer drug Discovery. Mini Rev Med Chem. 2021;21:2764–77.
3. Zhang D, Kanakkanthara A. Beyond the Paclitaxel and Vinca Alkaloids: next generation of plant-derived microtubule-targeting agents with potential anticancer activity. Cancers. 2020;12:1721.
4. Thomas CJ, Rahier NJ, Hecht SM. Camptothecin: current perspectives. Bioorg Med Chem. 2004;12:1585–604.
5. McKie SJ, Neuman KC, Maxwell A. DNA topoisomerases: advances in understanding of cellular roles and multi-protein complexes via structure-function analysis. BioEssays. 2021;43:e2000286.
6. Eng WK, Faucette L, Johnson RK, Sternglanz R. Evidence that DNA topoisomerase I is necessary for the cytotoxic effects of camptothecin. Mol Pharmacol. 1988;34:755–60.
7. Sandler A. Irinotecan plus cisplatin in small-cell lung cancer. Oncology. 2002;16:39–43.
8. Langer CJ. The emerging world role of irinotecan in lung cancer. Oncology. 2001;15:15–21.
9. Pectasides D, Mylonakis N, Farmakis D, Nikolaou M, Koumpou M, Katselis I, et al. Irinotecan and gemcitabine in patients with advanced non-small cell lung cancer, previously treated with cisplatin-based chemotherapy. A phase II study. Anticancer Res. 2003;23:4205–11.
10. Yang XQ, Li CY, Xu MF, Wang D. Comparison of first-line chemotherapy based on irinotecan or other drugs to treat non-small cell lung cancer in stage IIIB/IV: a systematic review and meta-analysis. BMC Cancer. 2015;15:949.
11. Reita D, Bour C, Benbrika R, Groh A, Pencreach E, Guérin E. Synergistic anti-tumor effect of mTOR inhibitors with irinotecan on colon cancer cells. Cancers. 2019;11:1581.
12. Gershenson DM. Irinotecan in epithelial ovarian cancer. Oncology. 2002;16:29–31.
13. Musa F, Pothuri B, Blank SV, et al. Phase II study of irinotecan in combination with bevacizumab in recurrent ovarian cancer. Gynecol Oncol. 2017;144:279–84.
14. Enzinger PC, Kulke MH, Clark JW, Ryan DP, Kim H, Earle CC, et al. A phase II trial of irinotecan in patients with previously untreated advanced esophageal and gastric adenocarcinoma. Dig Dis Sci. 2005;50:2218–23.
15. Verschraegen CF. Irinotecan for the treatment of cervical cancer. Oncology. 2002;16:32–4.
16. Mohammad AS, Griffith JI, Adkins CE, Shah N, Sechrest E, Dolan EL, et al. Liposomal irinotecan accumulates in metastatic lesions, crosses the blood-tumor barrier (BTB), and Prolongs Survival in an experimental model of Brain Metastases of Triple negative breast Cancer. Pharm Res. 2018;35:31.
17. Ocean AJ, Starodub AN, Bardia A, Vahdat LT, Isakoff SJ, Guarino M, et al. Sacituzumab govitecan (IMMU-132), an anti-Trop-2-SN-38 antibody-drug conjugate for the treatment of diverse epithelial cancers: Safety and pharmacokinetics. Cancer. 2017;123:3843–54.
18. Nakada T, Sugihara K, Jikoh T, Abe Y, Agatsuma T. The latest research and development into the antibody-drug Conjugate, [fam-] Trastuzumab Deruxtecan (DS-8201a), for HER2 Cancer therapy. Chem Pharm Bull. 2019;67:173–85.
19. Nair JJ, van Staden J. Cell cycle modulatory effects of Amaryllidaceae alkaloids. Life Sci. 2018;213:94–101.
20. Ingrassia L, Lefranc F, Dewelle J, Pottier L, Mathieu V, Spiegl-Kreinecker S. Structure-activity relationship analysis of novel derivatives of narciclasine (an Amaryllidaceae isocarbostyril derivative) as potential anticancer agents. J Med Chem. 2009;52:1100–14.
21. Dumont P, Ingrassia L, Rouzeau S, Ribaucour F, Thomas S, Roland I, et al. The Amaryllidaceae isocarbostyril narciclasine induces apoptosis by activation of the death receptor and/or mitochondrial pathways in cancer cells but not in normal fibroblasts. Neoplasia. 2007;9:766–76.
22. Van Goietsenoven G, Mathieu V, Lefranc F, Kornienko A, Evidente A, Kiss R. Narciclasine as well as other Amaryllidaceae isocarbostyrils are promising GTP-ase targeting agents against brain cancers. Med Res Rev. 2013;33:439–55.
23. Carrasco L, Fresno M, Vazquez D. Narciclasine: an antitumour alkaloid which blocks peptide bond formation by eukaryotic ribosomes. FEBS Lett. 1975;52:236–9.
24. Jimenez A, Sanchez L,Vazquez D. Location of resistance to the alkaloid narciclasine in the 60S ribosomal subunit. FEBS Lett. 1975;55:53–6.
25. Cao C, Huang W, Zhang N, Wu F, Xu T, Pan X. Narciclasine induces autophagy-dependent apoptosis in triple-negative breast cancer cells by regulating the AMPK-ULK1 axis. Cell Proliferation. 2018;51:e12518.
26. Fan TJ, Han LH, Cong RS, Liang J. Caspase family proteases and apoptosis. Acta Biochim Biophys Sin. 2005;37:719–27.
27. Aslan Koşar P, Tuncer H, Cihangir Uğuz A, Espino Palma J, et al. The efficiency of poly(ADP-Ribose) polymerase (PARP) cleavage on detection of apoptosis in an experimental model of testicular torsion. Int J Exp Pathol. 2015;96:294–300.
28. Choudhary GS, Al-Harbi S, Almasan A. Caspase-3 activation is a critical determinant of genotoxic stress-induced apoptosis. Methods Mol Biol. 2015;1219:1–9.
29. Wang Y, Luo W, Wang Y. PARP-1 and its associated nucleases in DNA damage response. DNA Repair. 2019;81:102651.
30. Cai T, Wu W, Guo L, Xia Y, Jiang X, Zhang L, et al. Notoginsenoside R1 induces DNA damage via PHF6 protein to inhibit cervical carcinoma cell proliferation. Mol Med Rep. 2021;23:242.
31. Pansare AV, Kulal DK, Shedge AA, Patil VR. Green synthesis of anticancerous honeycomb PtNPs clusters: their alteration effect on BSA and HsDNA using fluorescence probe. J Photochem Photobiol B. 2016;162:473–85.
32. Liu J, Geng G, Liang G, Wang L, Luo K, Yuan J. A novel topoisomerase I inhibitor DIA-001 induces DNA damage mediated cell cycle arrest and apoptosis in cancer cell. Ann Transl Med. 2020;8:89.
33. Jang JY, Kang YJ, Sung B, Kim MJ, Park C, Kang D, et al. MHY440, a Novel topoisomerase iota inhibitor, induces cell cycle arrest and apoptosis via a ROS-Dependent DNA damage signaling pathway in AGS Human gastric Cancer cells. Molecules. 2018;24:96.
34. Patra N, De U, Kang JA, Kim JM, Ahn MY, Lee J, et al. A novel epoxypropoxy flavonoid derivative and topoisomerase II inhibitor, MHY336, induces apoptosis in prostate cancer cells. Eur J Pharmacol. 2011;658:98–107.
35. Cowell IG, Austin CA. Visualization and quantification of topoisomerase-DNA covalent complexes using the trapped in agarose immunostaining (TARDIS) assay. Methods Mol Biol. 2018;1703:301–16.
36. Hassan NM, Alhossary AA, Mu Y, Kwoh CK. Protein-ligand blind docking using QuickVina-W with inter-process spatio-temporal integration. Sci Rep. 2017;7:15451.
37. Trott O, Olson AJ. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem. 2010;31:455–61.
38. Padget K, Carr R, Pearson AD,Tilby MJ, Austin CA. Camptothecin-stabilised topoisomerase I-DNA complexes in leukaemia cells visualised and quantified in situ by the TARDIS assay (trapped in agarose DNA immunostaining). Biochem Pharmacol. 2000;59:629–38.
39. Shieu MK, Ho HY, Lin CC, Lo YS, Chuang YC, Hsieh MJ, et al. Narciclasine suppresses oral cancer metastasis by modulating cathepsin B and extracellular signal-related kinase pathways. Biomed Pharmacother. 2023;158:114159.

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

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

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