title: HY-1 induces G(2)/M cell cycle arrest in human colon cancer cells through the ATR-Chk1-Cdc25C and Weel pathways.
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.
authors.affiliation: Institute of Nautical Medicine, Nantong University, Nantong, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhao
authors.forename: Zhonghua
authors.initials: Z
authors.lastname: Wu
authors.forename: Yuting
authors.initials: Y
authors.lastname: Zhang
authors.forename: Li
authors.initials: L
authors.lastname: Zhu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism; D016203:CDC2 Protein Kinase / Q000235:genetics / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D000071877:Checkpoint Kinase 1; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism; D004264:DNA Topoisomerases, Type I / Q000235:genetics / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000235:genetics / Q000378:metabolism; D018105:DNA, Kinetoplast / Q000235:genetics; D016195:G2 Phase / Q000187:drug effects*; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D045325:HCT116 Cells; D056945:Hep G2 Cells; D006801:Humans; D007624:KB Cells; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D059005:Topoisomerase II Inhibitors / Q000494:pharmacology; D020687:cdc25 Phosphatases / Q000235:genetics / Q000378:metabolism*
chemical_list: D018105:DNA, Kinetoplast; D059005:Topoisomerase II Inhibitors; C006004:N-phthalylglycine dimethylamide; D011494:Protein Kinases; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse; D016203:CDC2 Protein Kinase; C517009:CDC25C protein, human; D020687:cdc25 Phosphatases; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II; D005998:Glycine