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
IL-17 A is a promoter of colorectal cancer initiation and progression.Narciclasine is a polyhydroxy alkaloid compound isolated from Narcissus plants,which has potent anti-inflammatory and antitumor actions.The effects...IL-17 A is a promoter of colorectal cancer initiation and progression.Narciclasine is a polyhydroxy alkaloid compound isolated from Narcissus plants,which has potent anti-inflammatory and antitumor actions.The effects of narciclasine on colorectal tumors were evaluated,with a focus on IL-17 A.Narciclasine reduced the growth of HCT-116 and SW-480 colon cancer cells in vitro and in vivo in murine xenografts.The results of flow cytometry on JC-1 and Annexin V/PI revealed that narciclasine significantly reduced the mitochondrial membrane potential and induced apoptosis,findings confirmed by western blotting results of reduced Bcl2 and enhanced Bax expression,as well as accumulation of cleaved Caspase-3,Caspase-8,Caspase-9,and cytoplasmic Cytochrome-c.After narciclasine incubation,IL-17 A,Act1,and TRAF6 were down-regulated,while p-P65(Ser536)accumulated in the cytoplasm,a finding confirmed by laser scanning confocal microscopy.IL17A substitution could partly reverse these narciclasine effects while they were elevated by IL17A silencing.Moreover,IL-17 A,Act1,and TRAF6 were significantly expressed to greater extents in human colorectal cancer compared to normal adjacent tissue specimens and were closely linked with a poor prognosis.This study provided evidence that narciclasine may be a useful therapeutic drug for colorectal cancer treatment through its actions in down-regulating the L-17A/Act1/TRAF6/NF-kB anti-apoptotic signaling pathway.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.
基金the Shenzhen Science and Technology Plan(No.JCYJ20220530142009021)the National Natural Science Foundation of China(No.82060678,82060851,81760674)the Nanshan District of Shenzhen Science and Technology Project(China)(No.2019057).
文摘IL-17 A is a promoter of colorectal cancer initiation and progression.Narciclasine is a polyhydroxy alkaloid compound isolated from Narcissus plants,which has potent anti-inflammatory and antitumor actions.The effects of narciclasine on colorectal tumors were evaluated,with a focus on IL-17 A.Narciclasine reduced the growth of HCT-116 and SW-480 colon cancer cells in vitro and in vivo in murine xenografts.The results of flow cytometry on JC-1 and Annexin V/PI revealed that narciclasine significantly reduced the mitochondrial membrane potential and induced apoptosis,findings confirmed by western blotting results of reduced Bcl2 and enhanced Bax expression,as well as accumulation of cleaved Caspase-3,Caspase-8,Caspase-9,and cytoplasmic Cytochrome-c.After narciclasine incubation,IL-17 A,Act1,and TRAF6 were down-regulated,while p-P65(Ser536)accumulated in the cytoplasm,a finding confirmed by laser scanning confocal microscopy.IL17A substitution could partly reverse these narciclasine effects while they were elevated by IL17A silencing.Moreover,IL-17 A,Act1,and TRAF6 were significantly expressed to greater extents in human colorectal cancer compared to normal adjacent tissue specimens and were closely linked with a poor prognosis.This study provided evidence that narciclasine may be a useful therapeutic drug for colorectal cancer treatment through its actions in down-regulating the L-17A/Act1/TRAF6/NF-kB anti-apoptotic signaling pathway.
