| Inhibition of G1/S transition potentiates oxaliplatin-induced cell death in colon cancer cell lines. | |
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MedLine Citation:
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PMID: 17343830 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Tatiana V Rakitina; Irina A Vasilevskaya; Peter J O'Dwyer |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2007-02-04 |
Journal Detail:
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Title: Biochemical pharmacology Volume: 73 ISSN: 0006-2952 ISO Abbreviation: Biochem. Pharmacol. Publication Date: 2007 Jun |
Date Detail:
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Created Date: 2007-04-23 Completed Date: 2007-06-18 Revised Date: 2007-12-03 |
Medline Journal Info:
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Nlm Unique ID: 0101032 Medline TA: Biochem Pharmacol Country: England |
Other Details:
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Languages: eng Pagination: 1715-26 Citation Subset: IM |
Affiliation:
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Abramson Family Cancer Center, University of Pennsylvania, 1020 BRB II/III, 421 Curie Blvd, Philadelphia, PA 19104, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Cell Cycle
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drug effects Cell Death / drug effects* Colonic Neoplasms / pathology Drug Synergism G1 Phase / drug effects* Growth Inhibitors / pharmacology* Humans Organoplatinum Compounds / pharmacology* S Phase / drug effects* Tumor Cells, Cultured |
| Grant Support | |
ID/Acronym/Agency:
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CA 49820/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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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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