Abstract
The novel aroylthiourea analogue of podophyllotoxin HY-1 (4β-[benzoyl-thioureido]-4-deoxypodophyllotoxin) was synthesized in our laboratory with the aim of developing multitargeted DNA topoisomerase II inhibitors. The compound showed significant antiproliferative effects on seven cancer cell lines and induced G2 /M phase arrest in HCT116 cells. Moreover, HY-1 showed a potent inhibitory effect on topoisomerase II-mediated kinetoplast DNA decatenation in a dose-dependent manner. Our results showed that cdc2 phosphorylation and decreased cdc2 kinase acitivity through the ATR-Chk1-Cdc25C and Weel pathways were the central mechanisms for G2 /M phase arrest in human colon cancer cells.
© 2013 Japanese Cancer Association.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / drug effects
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Ataxia Telangiectasia Mutated Proteins / genetics
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Ataxia Telangiectasia Mutated Proteins / metabolism
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CDC2 Protein Kinase / genetics
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CDC2 Protein Kinase / metabolism
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Cell Cycle Checkpoints / drug effects*
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Cell Division / drug effects*
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cell Survival / drug effects
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Checkpoint Kinase 1
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Colonic Neoplasms / genetics*
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Colonic Neoplasms / metabolism
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DNA Topoisomerases, Type I / genetics
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DNA Topoisomerases, Type I / metabolism
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DNA Topoisomerases, Type II / genetics
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DNA Topoisomerases, Type II / metabolism
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DNA, Kinetoplast / genetics
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G2 Phase / drug effects*
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Glycine / analogs & derivatives*
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Glycine / pharmacology
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HCT116 Cells
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Hep G2 Cells
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Humans
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KB Cells
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Mice
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Phosphorylation / drug effects
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Protein Kinases / genetics
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Protein Kinases / metabolism*
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Topoisomerase II Inhibitors / pharmacology
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cdc25 Phosphatases / genetics
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cdc25 Phosphatases / metabolism*
Substances
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DNA, Kinetoplast
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Topoisomerase II Inhibitors
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N-phthalylglycine dimethylamide
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Protein Kinases
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ATR protein, human
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Ataxia Telangiectasia Mutated Proteins
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CHEK1 protein, human
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Checkpoint Kinase 1
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Chek1 protein, mouse
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CDC2 Protein Kinase
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CDC25C protein, human
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cdc25 Phosphatases
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DNA Topoisomerases, Type I
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DNA Topoisomerases, Type II
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Glycine