Document Detail

Selective Chk1 inhibitors differentially sensitize p53-deficient cancer cells to cancer therapeutics.
MedLine Citation:
PMID:  17019715     Owner:  NLM     Status:  MEDLINE    
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.
Zehan Chen; Zhan Xiao; Wen-Zhen Gu; John Xue; Mai H Bui; Peter Kovar; Gaoquan Li; Gary Wang; Zhi-Fu Tao; Yunsong Tong; Nan-Horng Lin; Hing L Sham; Jean Y J Wang; Thomas J Sowin; Saul H Rosenberg; Haiying Zhang
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  International journal of cancer. Journal international du cancer     Volume:  119     ISSN:  0020-7136     ISO Abbreviation:  Int. J. Cancer     Publication Date:  2006 Dec 
Date Detail:
Created Date:  2006-11-01     Completed Date:  2006-12-21     Revised Date:  2011-11-02    
Medline Journal Info:
Nlm Unique ID:  0042124     Medline TA:  Int J Cancer     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2784-94     Citation Subset:  IM    
Copyright Information:
Copyright 2006 Wiley-Liss, Inc.
Cancer Research, Abbott Laboratories, Abbott Park, IL 60064-6101, USA.
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MeSH Terms
Antibodies / pharmacology
Blotting, Western
CDC2 Protein Kinase / immunology,  metabolism
Camptothecin / pharmacology
Caspases / metabolism
Cell Cycle / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects,  radiation effects
Cell Survival / drug effects,  radiation effects
DNA Damage
Dose-Response Relationship, Drug
Doxorubicin / pharmacology
Drug Synergism
Hela Cells
Molecular Structure
Neoplasms / drug therapy,  metabolism,  pathology
Phosphorylation / drug effects
Protein Kinase Inhibitors / chemistry,  pharmacology*
Protein Kinases / genetics,  immunology,  metabolism*
Protein-Serine-Threonine Kinases / antagonists & inhibitors,  metabolism
RNA, Small Interfering / genetics
Time Factors
Tumor Suppressor Protein p53 / deficiency*,  genetics
Urea / analogs & derivatives*,  chemistry,  pharmacology
cdc25 Phosphatases / genetics,  metabolism
Reg. No./Substance:
0/A-641397; 0/A-690002; 0/Antibodies; 0/Protein Kinase Inhibitors; 0/RNA, Small Interfering; 0/Tumor Suppressor Protein p53; 23214-92-8/Doxorubicin; 57-13-6/Urea; 7689-03-4/Camptothecin; EC 2.7.-/Protein Kinases; EC kinase 1; EC Kinases; EC Protein Kinase; EC protein, human; EC Phosphatases; EC 3.4.22.-/Caspases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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