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...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_(2)/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.展开更多
基金the National Natural Science Foundation of China(Grant Nos.21907044,81460559 and 82160697)Yunnan Fundamental Research Projects(Grant Nos.202101AT070155 and 202201AS070086)+2 种基金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).
文摘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_(2)/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.
