Document Detail


Inhibited proliferation of cyclooxygenase-2 expressing human hepatoma cells by NS-398, a selective COX-2 inhibitor.
MedLine Citation:
PMID:  12632065     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Hepatocellular carcinoma (HCC) is a growing human health problem worldwide. Limited treatment and poor prognosis of this disease emphasize the importance in developing an effective chemoprevention. Overexpression of cyclooxygenase-2 (COX-2) has been associated with hepatocarcinogenesis. Although COX-2 inhibitors have been tested for chemoprevention of colon cancer, it remains unknown whether these agents possess anti-HCC effects as well. The present study assessed the effects of a selective COX-2 inhibitor, NS-398, on proliferation of human hepatoma cells in association with COX-2 expression, and the possible mechanisms. In four tested human hepatoma cell lines, overexpression of COX-2 was confirmed in HepG2, HuH7, and Chang liver cells, but not in PLC/PRF/5 cells. Addition of 50 micro M NS-398 resulted in both dose-dependent and time-course inhibition of HepG2 proliferation. In contrast, addition of 50 micro M NS-398 to COX-2 non-expressing PLC/PRF/5 cells resulted in only a mild reduction of cell proliferation. Consistent with this, a 48-h culture of HepG2 cells with 50 micro M NS-398 caused a significant decrease of prostaglandin E2 (PGE2) production. While, the same NS-398 treatment showed only a mild suppression of PGE2 production in COX-2 non-expressing PLC/PRF/5 cells. These findings indicate that NS-398-induced suppression of HepG2 proliferation appears mediated by decreased COX-2/prostaglandin (PG) production. We also found that NS-398-induced inhibition of HepG2 proliferation was associated with decreased 5-bromo-2'-deoxyuridine (BrdU) uptake, suggesting a reduced cell cycle progression in G1-S transition. NS-398 treatment also enhanced the apoptotic rate in COX-2 expressing HepG2 cells, but not in COX-2 non-expressing PLC/PRF/5 cells. Our findings confirmed an effective inhibitory effect of NS-398 on proliferation of COX-2 expressing human hepatoma cells through a decreased COX-2/PG activity that is associated with altered cell cycle progression and apoptotic rate.
Authors:
Ke-Qin Hu; Chang-Hong Yu; Yoshimitsu Mineyama; John D McCracken; Donald J Hillebrand; Mateen Hasan
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  International journal of oncology     Volume:  22     ISSN:  1019-6439     ISO Abbreviation:  Int. J. Oncol.     Publication Date:  2003 Apr 
Date Detail:
Created Date:  2003-03-12     Completed Date:  2003-11-17     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  9306042     Medline TA:  Int J Oncol     Country:  Greece    
Other Details:
Languages:  eng     Pagination:  757-63     Citation Subset:  IM    
Affiliation:
Loma Linda University Medical Center, Loma Linda, CA 92354, USA. khu@ahs.llumc.edu
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MeSH Terms
Descriptor/Qualifier:
Antimetabolites, Antineoplastic / pharmacology
Apoptosis
Bromodeoxyuridine / pharmacology
Carcinoma, Hepatocellular / enzymology*
Cell Cycle
Cell Division
Cell Line, Tumor
Cyclooxygenase 2
Cyclooxygenase 2 Inhibitors
Cyclooxygenase Inhibitors / pharmacology
Dinoprostone / metabolism
Dose-Response Relationship, Drug
Enzyme Inhibitors / pharmacology*
Humans
Immunohistochemistry
Isoenzymes / biosynthesis*
Membrane Proteins
Nitrobenzenes / pharmacology*
Prostaglandin-Endoperoxide Synthases / biosynthesis*
Sulfonamides / pharmacology*
Time Factors
Chemical
Reg. No./Substance:
0/Antimetabolites, Antineoplastic; 0/Cyclooxygenase 2 Inhibitors; 0/Cyclooxygenase Inhibitors; 0/Enzyme Inhibitors; 0/Isoenzymes; 0/Membrane Proteins; 0/Nitrobenzenes; 0/Sulfonamides; 123653-11-2/N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; 363-24-6/Dinoprostone; 59-14-3/Bromodeoxyuridine; EC 1.14.99.1/Cyclooxygenase 2; EC 1.14.99.1/PTGS2 protein, human; EC 1.14.99.1/Prostaglandin-Endoperoxide Synthases

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