title: 6,7-Dimethoxy-3-(3-methoxyphenyl)isoquinolin-1-amine induces mitotic arrest and apoptotic cell death through the activation of spindle assembly checkpoint in human cervical cancer cells.
abstract: Previously, we reported that 6,7-dimethoxy-3-(3-methoxyphenyl)isoquinolin-1-amine (CWJ-082) has potent cytotoxic effects on various cancer cells, but the underlying molecular mechanism responsible was not determined. In the present study, CWJ-082 caused cervical cancer cell cycle arrest at the G2/M phase and subsequent caspase-dependent apoptosis. The mitotic arrest caused by CWJ-082 found to be due to increases in the activation of cyclin-dependent kinase 1/cyclin B1 complex and the phosphorylation of histone H3. In addition, CWJ-082 induced the phosphorylation of BubR1 and the association between mitotic arrest deficient 2 (Mad2) and cell division cycle protein 20. These findings suggested that CWJ-082 activated the mitotic spindle checkpoint. Furthermore, knockdown of the spindle checkpoint proteins BubR1 or Mad2 using specific small interfering RNAs significantly reduced CWJ-082-induced mitotic cell accumulation and apoptosis. In addition, CWJ-082 induced the appearance of spindle abnormalities by inducing α-tubulin polymerization. In BALB/c(nu/nu) mice bearing a HeLa xenograft, CWJ-082 significantly inhibited tumor growth. Taken together, these results suggest that CWJ-082 inhibits cell growth via mitotic arrest by activating the mitotic spindle checkpoint and by inducing α-tubulin polymerization and that these events ultimately lead to the apoptosis of human cervical cancer cells and inhibit tumor growth in HeLa xenograft mice.
authors.affiliation: Department of Pharmaceutical Biochemistry, Reactive Oxygen Species Medical Research Center, School of Medicine, Kyung Hee University, Seoul, Republic of Korea.
authors.forename: Kyung-Sook
authors.initials: KS
authors.lastname: Chung
authors.forename: Hye-Eun
authors.initials: HE
authors.lastname: Choi
authors.forename: Ji-Sun
authors.initials: JS
authors.lastname: Shin
authors.forename: Young-Wuk
authors.initials: YW
authors.lastname: Cho
authors.forename: Jung-Hye
authors.initials: JH
authors.lastname: Choi
authors.forename: Won-Jea
authors.initials: WJ
authors.lastname: Cho
authors.forename: Kyung-Tae
authors.initials: KT
authors.lastname: Lee
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D016203:CDC2 Protein Kinase / Q000235:genetics / Q000378:metabolism; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D064199:Cdc20 Proteins / Q000235:genetics / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects* / Q000235:genetics; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D056744:Cyclin B1 / Q000235:genetics / Q000378:metabolism; D005260:Female; D016195:G2 Phase / Q000187:drug effects / Q000235:genetics; D006367:HeLa Cells; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology*; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects* / Q000235:genetics; D064246:Mad2 Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008870:Microtubules / Q000235:genetics / Q000378:metabolism; D008938:Mitosis / Q000187:drug effects* / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D014404:Tubulin / Q000235:genetics / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; C534699:CCNB1 protein, human; D064199:Cdc20 Proteins; D056744:Cyclin B1; D006657:Histones; D007546:Isoquinolines; C577697:MAD2L1 protein, human; D064246:Mad2 Proteins; D014404:Tubulin; C577488:CDC20 protein, human; C584277:BUB1 protein, human; D017346:Protein Serine-Threonine Kinases; D016203:CDC2 Protein Kinase; D020169:Caspases