title: Selective Chk1 inhibitors differentially sensitize p53-deficient cancer cells to cancer therapeutics.
abstract: The majority of cancer therapeutics induces DNA damage to kill cells. Normal proliferating cells undergo cell cycle arrest in response to DNA damage, thus allowing DNA repair to protect the genome. DNA damage induced cell cycle arrest depends on an evolutionarily conserved signal transduction network in which the Chk1 kinase plays a critical role. In mammalian cells, the p53 and RB pathways further augment the cell cycle arrest response to prevent catastrophic cell death. Given the fact that most tumor cells suffer defects in the p53 and RB pathways, it is likely that tumor cells would depend more on the Chk1 kinase to maintain cell cycle arrest than would normal cells. Therefore Chk1 inhibition could be used to specifically sensitize tumor cells to DNA-damaging agents. We have previously shown that siRNA-mediated Chk1 knockdown abrogates DNA damage-induced checkpoints and potentiates the cytotoxicity of several DNA-damaging agents in p53-deficient cell lines. In this study, we have developed 2 potent and selective Chk1 inhibitors, A-690002 and A-641397, and shown that these compounds abrogate cell cycle checkpoints and potentiate the cytotoxicity of topoisomerase inhibitors and gamma-radiation in p53-deficient but not in p53-proficient cells of different tissue origins. These results indicate that it is feasible to achieve a therapeutic window with 1 or more Chk1 inhibitors in potentiation of cancer therapy based on the status of the p53 pathway in a wide spectrum of tumor types.
authors.affiliation: Cancer Research, Abbott Laboratories, Abbott Park, IL 60064-6101, USA.
authors.forename: Zehan
authors.initials: Z
authors.lastname: Chen
authors.forename: Zhan
authors.initials: Z
authors.lastname: Xiao
authors.forename: Wen-Zhen
authors.initials: WZ
authors.lastname: Gu
authors.forename: John
authors.initials: J
authors.lastname: Xue
authors.forename: Mai H
authors.initials: MH
authors.lastname: Bui
authors.forename: Peter
authors.initials: P
authors.lastname: Kovar
authors.forename: Gaoquan
authors.initials: G
authors.lastname: Li
authors.forename: Gary
authors.initials: G
authors.lastname: Wang
authors.forename: Zhi-Fu
authors.initials: ZF
authors.lastname: Tao
authors.forename: Yunsong
authors.initials: Y
authors.lastname: Tong
authors.forename: Nan-Horng
authors.initials: NH
authors.lastname: Lin
authors.forename: Hing L
authors.initials: HL
authors.lastname: Sham
authors.forename: Jean Y J
authors.initials: JY
authors.lastname: Wang
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Sowin
authors.forename: Saul H
authors.initials: SH
authors.lastname: Rosenberg
authors.forename: Haiying
authors.initials: H
authors.lastname: Zhang
mesh_terms: D000906:Antibodies / Q000494:pharmacology; D015153:Blotting, Western; D016203:CDC2 Protein Kinase / Q000276:immunology / Q000378:metabolism; D002166:Camptothecin / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D000071877:Checkpoint Kinase 1; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D004357:Drug Synergism; D006367:HeLa Cells; D006801:Humans; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011494:Protein Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000235:genetics; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D020687:cdc25 Phosphatases / Q000235:genetics / Q000378:metabolism
chemical_list: C515626:A-641397; C515625:A-690002; D000906:Antibodies; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; D014508:Urea; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D017346:Protein Serine-Threonine Kinases; D016203:CDC2 Protein Kinase; C517004:CDC25A protein, human; D020687:cdc25 Phosphatases; D020169:Caspases; D002166:Camptothecin