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


METHODS
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.
Nam
Ki Taek
KT
Department of General Toxicology, National Institute of Toxicological Research, Korea Food and Drug Administration, Seoul, Korea.
Hahm
Ki-Baik
KB
Oh
Sang-Yeon
SY
Yeo
Marie
M
Han
Sang-Uk
SU
Ahn
Byeongwoo
B
Kim
Young-Bae
YB
Kang
Jin Seok
JS
Jang
Dong Deuk
DD
Yang
Ki-Hwa
KH
Kim
Dae-Yong
DY
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use*; D005753:Gastric Mucosa / Q000382:microbiology; D016481:Helicobacter Infections / Q000150:complications* / Q000188:drug therapy / Q000473:pathology; D016480:Helicobacter pylori / Q000472:pathogenicity*; D020287:In Situ Nick-End Labeling; D008297:Male; D008770:Methylnitrosourea / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D011451:Prostaglandin-Endoperoxide Synthases / Q000737:chemistry* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013274:Stomach Neoplasms / Q000139:chemically induced / Q000382:microbiology / Q000517:prevention & control*; D013449:Sulfonamides / Q000627:therapeutic use*; D051028:bcl-2-Associated X Protein
C494827:Bax protein, mouse; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D051028:bcl-2-Associated X Protein; D008770:Methylnitrosourea; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C012655:nimesulide