Document Detail

Epigenetic mechanisms of irinotecan sensitivity in colorectal cancer cell lines.
MedLine Citation:
PMID:  19531575     Owner:  NLM     Status:  MEDLINE    
Irinotecan is a topoisomerase-I (Top-I) inhibitor used for the treatment of colorectal cancer. DNA demethylating agents, including 5-azacytidine (5-aza), display synergistic antitumor activity with several chemotherapy drugs. 5-Aza may enhance irinotecan cytotoxicity by at least one of the following mechanisms: (a) Top-I promoter demethylation, (b) activation of genes involved in Top-I transcriptional regulation (p16 or Sp1), and (c) modulation of the cell cycle and apoptosis after DNA damage. The growth-inhibitory effects of SN38, the active metabolite of irinotecan, 5-aza, and their combinations, were studied in four colorectal cancer cell lines. The effects of treatments on cell cycle were analyzed by flow cytometry, and apoptosis was measured by fluorescence microscopy. Top-I, Sp1, and p53 expression modulated by 5-aza were measured by real-time PCR. Methylation of Top-I, p16, 14-3-3sigma, and hMLH1 promoters before and after 5-aza treatment were measured by MethyLight PCR and DNA bisulfite sequencing. Low-dose 5-aza significantly enhanced the apoptotic effect of irinotecan in all colorectal cancer cells, whereas a synergistic cytotoxic effect was observed only in p53-mutated cells (HT29, SW620, and WiDr). This synergistic effect was significantly correlated with Top-I up-regulation by 5-aza, and coupled to p16 demethylation and Sp1 up-regulation. p16 demethylation was also associated with enhanced cell cycle arrest after irinotecan treatment. In contrast, 5-aza down-regulated Top-I expression in the p53 wild-type LS174T cells in a p53-dependent manner, thereby reducing SN38 cytotoxicity. In conclusion, 5-aza modulates Top-I expression by several mechanisms involving Sp1, p16, and p53. If confirmed in other models, these results suggest that p16 and p53 status affects the 5-aza-irinotecan interaction.
Francesco Crea; Elisa Giovannetti; Filippo Cortesi; Valentina Mey; Sara Nannizzi; Marielle I Gallegos Ruiz; Simona Ricciardi; Mario Del Tacca; Godefridus J Peters; Romano Danesi
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Publication Detail:
Type:  Journal Article     Date:  2009-06-16
Journal Detail:
Title:  Molecular cancer therapeutics     Volume:  8     ISSN:  1538-8514     ISO Abbreviation:  Mol. Cancer Ther.     Publication Date:  2009 Jul 
Date Detail:
Created Date:  2009-07-15     Completed Date:  2009-10-19     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101132535     Medline TA:  Mol Cancer Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1964-73     Citation Subset:  IM    
Scuola Superiore Sant'Anna, Pisa, Italy.
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MeSH Terms
14-3-3 Proteins / genetics,  metabolism
Antimetabolites, Antineoplastic / pharmacology
Antineoplastic Agents, Phytogenic / pharmacology*
Azacitidine / pharmacology
Camptothecin / analogs & derivatives*,  pharmacology
Cell Cycle / drug effects
Cell Proliferation / drug effects
Colorectal Neoplasms / drug therapy*,  genetics*,  pathology
Cyclin-Dependent Kinase Inhibitor p16 / genetics,  metabolism
DNA Damage / drug effects
DNA Methylation*
DNA Topoisomerases, Type I / genetics,  metabolism
Drug Therapy, Combination
Epigenesis, Genetic*
RNA, Messenger / genetics,  metabolism
Reverse Transcriptase Polymerase Chain Reaction
Tumor Cells, Cultured
Tumor Suppressor Protein p53 / genetics,  metabolism
Reg. No./Substance:
0/14-3-3 Proteins; 0/Antimetabolites, Antineoplastic; 0/Antineoplastic Agents, Phytogenic; 0/Cyclin-Dependent Kinase Inhibitor p16; 0/RNA, Messenger; 0/TP53 protein, human; 0/Tumor Suppressor Protein p53; 100286-90-6/irinotecan; 320-67-2/Azacitidine; 7689-03-4/Camptothecin; EC Topoisomerases, Type I

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