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.
Copyright © 2012 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / pharmacology*
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Aurora Kinase B
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Aurora Kinases
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CDC2 Protein Kinase / antagonists & inhibitors
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CDC2 Protein Kinase / metabolism
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Caspases / metabolism
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Cell Cycle Checkpoints / drug effects*
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Cell Cycle Checkpoints / physiology
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Cell Survival / drug effects
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Chromosomal Proteins, Non-Histone / antagonists & inhibitors
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Chromosomal Proteins, Non-Histone / metabolism
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Cyclin B1 / antagonists & inhibitors
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Cyclin B1 / metabolism
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Flow Cytometry
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HL-60 Cells
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Humans
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Inhibitory Concentration 50
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Leukemia / drug therapy*
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Leukemia / metabolism
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Leukemia / pathology
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Microtubules / metabolism*
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Mitosis / drug effects*
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Mitosis / physiology
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Naphthyridines / pharmacology*
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins c-bcl-2 / metabolism
Substances
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Antineoplastic Agents
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CCNB1 protein, human
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Chromosomal Proteins, Non-Histone
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Cyclin B1
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Naphthyridines
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Proto-Oncogene Proteins c-bcl-2
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centromere protein E
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AURKB protein, human
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Aurora Kinase B
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Aurora Kinases
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Protein Serine-Threonine Kinases
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CDC2 Protein Kinase
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Caspases