Celecoxib inhibits apurinic/apyrimidinic endonuclease-1 expression and prevents gastric cancer in Helicobacter pylori-infected mongolian gerbils.
OBJECTIVE
The aim of this study was to see whether administration of celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, could prevent the development of gastric cancer via inhibition of apurinic/apyrimidinic endonuclease-1 (APE-1) expression induced by Helicobacter pylori infection.


METHODS
70 Mongolian gerbils were divided into 6 groups. Group 1 gerbils served as controls (n = 6). Ten gerbils were given N-methyl-N-nitrosourea (MNU), 30 ppm, 5 times biweekly (group 2). Short-term H. pylori infection was induced in 6 gerbils which were sacrificed 8 weeks after H. pylori infection (group 3). Long-term H. pylori infection was induced in 6 other gerbils which were sacrificed 44 weeks after H. pylori infection (group 4). Twenty gerbils were given MNU pretreatment 5 times biweekly and long-term H. pylori infection (group 5). In addition, after H. pylori inoculation, group 6 gerbils also received celecoxib with their diet for 26 weeks. APE-1 expression alone or with COX-2 in gastric tissues was evaluated by Western blot and immunohistological analysis. Myeloperoxidase (MPO) activity and thiobarbituric-acid-reactive substance (TBARS) levels were also evaluated.


RESULTS
APE-1 was localized in gastric epithelial cells and mesenchymal cells including macrophages in H. pylori-infected gerbils. The numbers of APE-1-positive cells in group 4 and 5 were significantly increased compared to those of group 3. Celecoxib treatment significantly reduced MPO activity, TBARS levels and the incidence of gastric cancer. APE-1 and IkappaBalpha phosphorylation levels were significantly increased in MNU-pretreated H. pylori-infected gerbils compared to those in MNU-only gerbils. Celecoxib significantly reduced APE-1 and IkappaBalpha phosphorylation levels in MNU-pretreated H. pylori-infected gerbils. COX-2 and APE-1 were coexpressed in the macrophages of H. pylori-infected gerbils.


CONCLUSIONS
Celecoxib prevented gastric cancer in MNU-pretreated H. pylori-infected gerbils with a reduction in APE-1 expression thereby suggesting the implication of APE-1 in gastric carcinogenesis in this model.
Futagami
Seiji
S
Division of Gastroenterology, Nippon Medical School, Tokyo, Japan. seiji.futagami@gmail.com
Kawagoe
Tetsuro
T
Horie
Akane
A
Shindo
Tomotaka
T
Hamamoto
Tatsuhiko
T
Suzuki
Kenji
K
Kusunoki
Masafumi
M
Miyake
Kazumasa
K
Gudis
Katya
K
Tsukui
Taku
T
Crowe
Sheila E
SE
Sakamoto
Choitsu
C
D000818:Animals; D000068579:Celecoxib; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage*; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000096:biosynthesis* / Q000235:genetics; D018450:Disease Progression; D015870:Gene Expression / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic; D005849:Gerbillinae; D016481:Helicobacter Infections / Q000150:complications / Q000378:metabolism*; D008297:Male; D011720:Pyrazoles / Q000008:administration & dosage*; D013274:Stomach Neoplasms / Q000209:etiology / Q000517:prevention & control*; D013449:Sulfonamides / Q000008:administration & dosage*
D016861:Cyclooxygenase Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D000068579:Celecoxib