Document Detail


Zebularine suppresses the apoptotic potential of 5-fluorouracil via cAMP/PKA/CREB pathway against human oral squamous cell carcinoma cells.
MedLine Citation:
PMID:  18830594     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
PURPOSE: During tumorigenesis, tumor suppressor and tumor-related genes are commonly silenced by aberrant DNA methylation in their promoter regions, which is one of the important determinants of susceptibility to 5-fluorouracil (5-FU) in oral squamous cell carcinoma (OSCC) cells. Here, we examine the chemotherapeutic efficacy of epigenetic agents on 5-FU cytotoxicity.
METHOD: We investigated the effect of a DNA methyltransferase (DNMT) inhibitor, zebularine (Zeb), on the chemosensitivity of 5-FU and cisplatin (CDDP) by MTT and TUNEL methods, and compared the molecular mechanism of action with those of a GSK3beta inhibitor, LiCl, and an Hsp90 inhibitor, 17-AAG.
RESULTS: A significant apoptotic effect by a combination of Zeb or 17-AAG was found in CDDP treatment; however, considerable suppression of 5-FU-induced apoptosis was observed after incubation with Zeb, 17-AAG, or LiCl. Zeb's suppressive effects were associated with activation of the cAMP/PKA/CREB pathway, differing from mechanisms of 17-AAG and LiCl. Suppression of 5-FU-induced apoptosis by Zeb was not associated with increased Bcl-2 and Bcl-xL expressions dependent on transcription factor CREB, and with the expression level of thymidylate synthase.
CONCLUSIONS: In the present study, we identified a more detailed mechanism of action by which Zeb suppresses 5-FU-induced apoptosis. These results indicate that combination therapies have to be carefully investigated due to potential harmful effects in the clinical application of DNMT inhibitors.
Authors:
Maiko Suzuki; Fumiaki Shinohara; Manabu Endo; Masaki Sugazaki; Seishi Echigo; Hidemi Rikiishi
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-10-02
Journal Detail:
Title:  Cancer chemotherapy and pharmacology     Volume:  64     ISSN:  1432-0843     ISO Abbreviation:  Cancer Chemother. Pharmacol.     Publication Date:  2009 Jul 
Date Detail:
Created Date:  2009-06-01     Completed Date:  2009-06-15     Revised Date:  2011-11-02    
Medline Journal Info:
Nlm Unique ID:  7806519     Medline TA:  Cancer Chemother Pharmacol     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  223-32     Citation Subset:  IM    
Affiliation:
Department of Microbiology and Immunology, Tohoku University Graduate School of Dentistry, 4-1 Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan.
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MeSH Terms
Descriptor/Qualifier:
Adjuvants, Immunologic / pharmacology
Antimetabolites, Antineoplastic / pharmacology
Antineoplastic Agents / pharmacology
Apoptosis / drug effects*
Benzoquinones / pharmacology
Blotting, Western
Carcinoma, Squamous Cell / drug therapy,  metabolism,  pathology
Cell Line, Tumor
Cisplatin / pharmacology
Cyclic AMP Response Element-Binding Protein / antagonists & inhibitors,  metabolism*
Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors,  metabolism*
Cytidine / analogs & derivatives*,  pharmacology
DNA (Cytosine-5-)-Methyltransferase / antagonists & inhibitors
Fluorouracil / antagonists & inhibitors*,  pharmacology
Glycogen Synthase Kinase 3 / antagonists & inhibitors,  metabolism
HSP90 Heat-Shock Proteins / antagonists & inhibitors,  metabolism
Humans
In Situ Nick-End Labeling
Lactams, Macrocyclic / pharmacology
Lithium Chloride / pharmacology
Mouth Neoplasms / drug therapy*,  metabolism,  pathology
NF-kappa B / metabolism
Phosphorylation / drug effects
Proto-Oncogene Proteins c-bcl-2 / metabolism
Signal Transduction / drug effects
Chemical
Reg. No./Substance:
0/17-(allylamino)-17-demethoxygeldanamycin; 0/Adjuvants, Immunologic; 0/Antimetabolites, Antineoplastic; 0/Antineoplastic Agents; 0/Benzoquinones; 0/CREB1 protein, human; 0/Cyclic AMP Response Element-Binding Protein; 0/HSP90 Heat-Shock Proteins; 0/Lactams, Macrocyclic; 0/NF-kappa B; 0/Proto-Oncogene Proteins c-bcl-2; 15663-27-1/Cisplatin; 3690-10-6/pyrimidin-2-one beta-ribofuranoside; 51-21-8/Fluorouracil; 65-46-3/Cytidine; 7447-41-8/Lithium Chloride; EC 2.1.1.37/DNA (Cytosine-5-)-Methyltransferase; EC 2.7.11.1/glycogen synthase kinase 3 beta; EC 2.7.11.11/Cyclic AMP-Dependent Protein Kinases; EC 2.7.11.26/Glycogen Synthase Kinase 3

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