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The selective cyclooxygenase-2 inhibitor nimesulide prevents Helicobacter pylori-associated gastric cancer development in a mouse model.

Authors
Nam, KT; Hahm, KB; Oh, SY; Yeo, M; Han, SU; Ahn, B; Kim, YB; Kang, JS; Jang, DD; Yang, KH; Kim, DY
Citation
Clinical cancer research : an official journal of the American Association for Cancer Research, 10(23):8105-8113, 2004
Journal Title
Clinical cancer research : an official journal of the American Association for Cancer Research
ISSN
1078-0432
Abstract
PURPOSE: Helicobacter pylori infection can lead to gastric cancer, and cyclooxygenase-2 (COX-2) is overexpressed in the stomach during H. pylori infection. Therefore, we investigated whether nonsteroidal anti-inflammatory drugs might protect against this form of cancer. Specifically, we examined the chemopreventive effect of the COX-2 inhibitor nimesulide on H. pylori-associated gastric carcinogenesis in mice.



EXPERIMENTAL DESIGN: C57BL/6 mice were treated with the carcinogen N-methyl-N-nitrosourea (MNU) and/or H. pylori. To determine the effect of COX-2 inhibition, nimesulide was mixed with feed pellets and administered for the duration of the experiment. All of the mice were sacrificed 50 weeks after the start of the experiment. Histopathology, immunohistochemistry, and Western blotting for COX-2, Bax and Bcl-2 were performed in stomach tissues. In vitro experiments with the human gastric cancer cell line AGS were also performed to identify mechanisms underlying cancer chemoprevention by nimesulide.



RESULTS: Gastric tumors developed in 68.8% of mice that were given both MNU and H. pylori, whereas less than 10% developed gastric tumors when given either MNU or H. pylori alone. These findings indicate that H. pylori promotes carcinogen-induced gastric tumorigenesis. In mice treated with both MNU and H. pylori, nimesulide administration substantially reduced H. pylori-associated gastric tumorigenesis, whereas substantial inductions of apoptosis were observed. In vitro studies demonstrated that nimesulide and H. pylori when combined acted synergistically to induce more apoptosis than either alone.



CONCLUSIONS: Our data show that nimesulide prevents H. pylori-associated gastric carcinogenesis, and suggest that COX-2 may be a target for chemoprevention of gastric cancer.
MeSH terms
AnimalsApoptosis/drug effectsBlotting, WesternCyclooxygenase 2Cyclooxygenase 2 InhibitorsCyclooxygenase Inhibitors/*therapeutic useGastric Mucosa/microbiologyHelicobacter Infections/*complications/drug therapy/pathologyHelicobacter pylori/*pathogenicityIn Situ Nick-End LabelingMaleMethylnitrosourea/toxicityMiceMice, Inbred C57BLProstaglandin-Endoperoxide Synthases/*chemistry/metabolismProto-Oncogene Proteins c-bcl-2/metabolismStomach Neoplasms/chemically induced/microbiology/*prevention & controlSulfonamides/*therapeutic usebcl-2-Associated X Protein
DOI
10.1158/1078-0432.CCR-04-0896
PMID
15585646
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Gastroenterology
Journal Papers > School of Medicine / Graduate School of Medicine > Surgery
Journal Papers > School of Medicine / Graduate School of Medicine > Pathology
AJOU Authors
함, 기백한, 상욱김, 영배
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