Document Detail


The position of the amino group on the benzene ring is critical for mesalamine's improvement of replication fidelity.
MedLine Citation:
PMID:  19821510     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Individuals with ulcerative colitis are at high risk of developing colitis-associated cancer. 5-Aminosalicylate (5-ASA) protects from cancer by its antiinflammatory activity as well as by altering cell growth, inducing apoptosis, and reducing replication errors. So far neither 5-ASA's structural specificity nor its pharmacophore group have been identified. Here we compared 5-ASA with its analogs (4-ASA and 3-ASA) and its metabolite N-acetyl-5-ASA (NAc-5-ASA).
METHODS: Superoxide scavenging was analyzed by lucigenin-amplified chemiluminescence. Cell growth, cell cycle distribution, and replication fidelity at a (CA)13 microsatellite were measured in HCT116 and HT29 colon epithelial cells by MTT and flow cytometry. Nuclear protein extracts were blotted for replication protein A (RPA), claspin, p53, and p53(Ser15).
RESULTS: All compounds inhibited the growth of colon epithelial cells at a similar level and displayed potent scavenging properties, with 3-ASA being the most active, followed by 5-ASA, 4-ASA, and NAc-5-ASA. Besides 5-ASA, only 4-ASA caused an increase in the S-phase population (56%-69% and 49%-62% in HCT116 and HT29 cells, respectively). This was accompanied by nuclear recruitment of replication proteins RPA and claspin as well as phosphorylation of p53(Ser15), both of which were weaker or absent with 3-ASA or NAc-5-ASA. 5-ASA was the only compound that lowered mutations at a (CA)13 microsatellite.
CONCLUSIONS: 5-ASA shares its growth inhibitory and superoxide scavenging properties with its structural analogs and metabolite, but the position of the amino group is critical for reducing replication errors.
Authors:
Christoph Campregher; Maria Gloria Luciani; Peter Biesenbach; Rayko Evstatiev; Alex Lyakhovich; Christoph Gasche
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Inflammatory bowel diseases     Volume:  16     ISSN:  1536-4844     ISO Abbreviation:  Inflamm. Bowel Dis.     Publication Date:  2010 Apr 
Date Detail:
Created Date:  2010-03-23     Completed Date:  2010-07-27     Revised Date:  2011-04-06    
Medline Journal Info:
Nlm Unique ID:  9508162     Medline TA:  Inflamm Bowel Dis     Country:  United States    
Other Details:
Languages:  eng     Pagination:  576-82     Citation Subset:  IM    
Affiliation:
Medical University of Vienna, Department of Internal Medicine III, Division of Gastroenterology and Hepatology, and Christian Doppler Laboratory on Molecular Cancer Chemoprevention, Vienna, Austria.
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MeSH Terms
Descriptor/Qualifier:
Adaptor Proteins, Signal Transducing / metabolism
Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
Benzene / chemistry*
Blotting, Western
Cell Cycle / drug effects
Cell Proliferation / drug effects
DNA Replication / drug effects*
Flow Cytometry
HT29 Cells / drug effects
Humans
Mesalamine / pharmacology*
Microsatellite Repeats
Neutrophils / metabolism
Replication Protein A / metabolism*
Superoxides / metabolism
Tumor Suppressor Protein p53 / metabolism
Grant Support
ID/Acronym/Agency:
P 18270-B14//Austrian Science Fund FWF
Chemical
Reg. No./Substance:
0/Adaptor Proteins, Signal Transducing; 0/Anti-Inflammatory Agents, Non-Steroidal; 0/CLSPN protein, human; 0/Replication Protein A; 0/TP53 protein, human; 0/Tumor Suppressor Protein p53; 11062-77-4/Superoxides; 71-43-2/Benzene; 89-57-6/Mesalamine

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