Document Detail

Inhibition of G1/S transition potentiates oxaliplatin-induced cell death in colon cancer cell lines.
MedLine Citation:
PMID:  17343830     Owner:  NLM     Status:  MEDLINE    
In a series of colorectal cancer cell lines, both necrosis and apoptosis were induced upon exposure to oxaliplatin, and enhanced by co-administration of the Hsp90 inhibitor 17-AAG. We analyzed the effects of these interventions on the cell cycle, and found that oxaliplatin treatment caused G1 and G2 arrest in HCT116 cells, and S-phase accumulation in two p53-deficient cell lines (HT29 and DLD1). Addition of 17-AAG enhanced cell cycle effects of oxaliplatin in HCT116, and induced G1 arrest and decrease in S-phase population in the other cell lines. Analysis of cell cycle proteins revealed that the major difference between the cell lines was that in HCT116, 17-AAG resulted in profound inhibition of expression and phosphorylation of late G1 proteins cyclin E and cdk2, with no effect on p21/WAF1 induction. Consistent with these, an HCT116 p53(-/-) line, lacking p21, showed resistance to oxaliplatin, failure to enter apoptosis, and an accumulation of cells in S-phase. Introduction of p21 in these cells caused reversal of that phenotype, including restoration of the G1 block and re-sensitization to oxaliplatin. Inhibition of G1/S progression using cdk2 inhibitor also enhanced oxaliplatin cytotoxicity. We conclude that in colon cancer cells with impaired p53 function, interventions directed to cycle arrest in G1 may potentiate oxaliplatin activity.
Tatiana V Rakitina; Irina A Vasilevskaya; Peter J O'Dwyer
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2007-02-04
Journal Detail:
Title:  Biochemical pharmacology     Volume:  73     ISSN:  0006-2952     ISO Abbreviation:  Biochem. Pharmacol.     Publication Date:  2007 Jun 
Date Detail:
Created Date:  2007-04-23     Completed Date:  2007-06-18     Revised Date:  2007-12-03    
Medline Journal Info:
Nlm Unique ID:  0101032     Medline TA:  Biochem Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  1715-26     Citation Subset:  IM    
Abramson Family Cancer Center, University of Pennsylvania, 1020 BRB II/III, 421 Curie Blvd, Philadelphia, PA 19104, USA.
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MeSH Terms
Cell Cycle / drug effects
Cell Death / drug effects*
Colonic Neoplasms / pathology
Drug Synergism
G1 Phase / drug effects*
Growth Inhibitors / pharmacology*
Organoplatinum Compounds / pharmacology*
S Phase / drug effects*
Tumor Cells, Cultured
Grant Support
Reg. No./Substance:
0/Growth Inhibitors; 0/Organoplatinum Compounds; 63121-00-6/oxaliplatin

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

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