Document Detail

Knockdown of Chk1 sensitizes human colon carcinoma HCT116 cells in a p53-dependent manner to lidamycin through abrogation of a G2/M checkpoint and induction of apoptosis.
MedLine Citation:
PMID:  19502782     Owner:  NLM     Status:  MEDLINE    
Recent advances in cell cycle regulation have led to a suggestion of therapeutically targeting cell cycle checkpoint pathways in cancer cells to increase the toxicity of DNA-damaging agents. In this study, we investigate whether knockdowns of checkpoint kinases Chk1 and Chk2 by RNA interfering potentiate the cytotoxicity and abrogate G(2)/M checkpoint induced by DNA-damaging agent lidamycin (LDM) in HCT116 cells with different p53 status. Our results showed that Chk1 knockdown enhanced the cytotoxicity of LDM through abrogating G(2)/M arrest and increasing apoptosis to a greater extent in HCT116 p53(-/-) cells than in p53(wt) cells. Abrogation of LDM-induced G(2)/M arrest by Chk1 knockdown was associated with reducing the inactivated phosphorylations of Cdc25C and Cdc2. LDM-induced gamma-H2AX was increased in cells with Chk1 knockdown, indicating that DNA double-strand breaks (DSBs) were enhanced. Furthermore, knockdown of Chk1 also increased LDM-mediated apoptotic cell death in p53 knockout cells with activation of caspase-2 and caspase-3. On the contrary, knockdown of Chk2 had no impact on G(2)/M arrest or apoptosis induced by LDM. Moreover, dual knockdown of Chk1 and Chk2 failed to achieve better efficacy than Chk1 alone. Taken together, we suggest that Chk1 is a potential therapeutic target to sensitize human p53 deficient cancer cells to LDM.
Yu Pan; Kai-Huan Ren; Hong-Wei He; Rong-Guang Shao
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-08-08
Journal Detail:
Title:  Cancer biology & therapy     Volume:  8     ISSN:  1555-8576     ISO Abbreviation:  Cancer Biol. Ther.     Publication Date:  2009 Aug 
Date Detail:
Created Date:  2009-10-13     Completed Date:  2010-02-12     Revised Date:  2011-11-02    
Medline Journal Info:
Nlm Unique ID:  101137842     Medline TA:  Cancer Biol Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1559-66     Citation Subset:  IM    
Department of oncology, Institute of Medicinal Biotechnology, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
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MeSH Terms
Aminoglycosides / pharmacology*
Antibiotics, Antineoplastic / pharmacology*
Apoptosis / genetics
Blotting, Western
Caspase 2 / metabolism
Caspase 3 / metabolism
Cell Cycle Proteins / genetics,  metabolism
Cell Division / drug effects,  genetics
Cell Growth Processes / drug effects,  genetics
Colonic Neoplasms / drug therapy*,  enzymology*,  genetics,  pathology
Cysteine Endopeptidases / metabolism
Enediynes / pharmacology*
G2 Phase / drug effects,  genetics
Gene Knockdown Techniques
HCT116 Cells
Protein Kinase Inhibitors / pharmacology
Protein Kinases / deficiency*,  genetics,  metabolism
Protein-Serine-Threonine Kinases / deficiency,  genetics,  metabolism
RNA, Small Interfering / genetics
Tumor Suppressor Protein p53 / metabolism*
Reg. No./Substance:
0/Aminoglycosides; 0/Antibiotics, Antineoplastic; 0/Cell Cycle Proteins; 0/Enediynes; 0/Protein Kinase Inhibitors; 0/RNA, Small Interfering; 0/TP53 protein, human; 0/Tumor Suppressor Protein p53; 120177-69-7/C 1027; EC 2.7.-/Protein Kinases; EC kinase 2; EC kinase 1; EC Kinases; EC 3.4.22.-/CASP2 protein, human; EC 3.4.22.-/Caspase 2; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Cysteine Endopeptidases

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