title: 2-(3-Methoxyphenyl)-5-methyl-1,8-naphthyridin-4(1H)-one (HKL-1) induces G2/M arrest and mitotic catastrophe in human leukemia HL-60 cells.
abstract: 2-(3-Methoxyphenyl)-5-methyl-1,8-naphthyridin-4(1H)-one (HKL-1), a 2-phenyl-1,8-naphthyridin-4-one (2-PN) derivative, was synthesized and evaluated as an effective antimitotic agent in our laboratory. However, the molecular mechanisms are uncertain. In this study, HKL-1 was demonstrated to induce multipolar spindles, sustain mitotic arrest and generate multinucleated cells, all of which indicate mitotic catastrophe, in human leukemia HL-60 cells. Western blotting showed that HKL-1 induces mitotic catastrophe in HL-60 cells through regulating mitotic phase-specific kinases (down-regulating CDK1, cyclin B1, CENP-E, and aurora B) and regulating the expression of Bcl-2 family proteins (down-regulating Bcl-2 and up-regulating Bax and Bak), followed by caspase-9/-3 cleavage. These findings suggest that HKL-1 appears to exert its cytotoxicity toward HL-60 cells in culture by inducing mitotic catastrophe.
authors.affiliation: Graduate Institute of Pharmaceutical Chemistry, China Medical University, Taichung, Taiwan, ROC.
authors.forename: Mei-Hua
authors.initials: MH
authors.lastname: Hsu
authors.forename: Chin-Yu
authors.initials: CY
authors.lastname: Liu
authors.forename: Chiao-Min
authors.initials: CM
authors.lastname: Lin
authors.forename: Yen-Jung
authors.initials: YJ
authors.lastname: Chen
authors.forename: Chun-Jen
authors.initials: CJ
authors.lastname: Chen
authors.forename: Yu-Fu
authors.initials: YF
authors.lastname: Lin
authors.forename: Li-Jiau
authors.initials: LJ
authors.lastname: Huang
authors.forename: Kuo-Hsiung
authors.initials: KH
authors.lastname: Lee
authors.forename: Sheng-Chu
authors.initials: SC
authors.lastname: Kuo
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D064107:Aurora Kinase B; D064127:Aurora Kinases; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects* / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D002868:Chromosomal Proteins, Non-Histone / Q000037:antagonists & inhibitors / Q000378:metabolism; D056744:Cyclin B1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D005434:Flow Cytometry; D018922:HL-60 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D007938:Leukemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008870:Microtubules / Q000378:metabolism*; D008938:Mitosis / Q000187:drug effects* / Q000502:physiology; D009287:Naphthyridines / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C534699:CCNB1 protein, human; D002868:Chromosomal Proteins, Non-Histone; D056744:Cyclin B1; D009287:Naphthyridines; D019253:Proto-Oncogene Proteins c-bcl-2; C068688:centromere protein E; C576921:AURKB protein, human; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D016203:CDC2 Protein Kinase; D020169:Caspases