A prostaglandin E2 receptor subtype EP1-selective antagonist, ONO-8711, suppresses 4-nitroquinoline 1-oxide-induced rat tongue carcinogenesis.
We previously reported that certain cyclooxygenase (COX) inhibitors could inhibit chemically induced tongue carcinogenesis. In the present study, we investigated the effects of prostaglandin E(2) (PGE(2)) receptor EP(1)-selective antagonist ONO-8711 on 4-nitroquinoline 1-oxide (4-NQO)-induced oral carcinogenesis to know whether an EP(1) receptor involves in oral carcinogenesis. Male Fischer 344 rats were given drinking water containing 4-NQO for 8 weeks (20 p.p.m. for the initial 2 weeks, 25 p.p.m. for 2 weeks, and then 30 p.p.m. for 4 weeks). After 4-NQO treatment, animals were given 400 or 800 p.p.m. ONO-8711 containing diets for 23 weeks. The incidence of tongue squamous cell carcinomas (SCC) in the 4-NQO-treated rats was 64%, while that in the rats given ONO-8711 after 4-NQO exposure was 29 (P<0.05) and 29% (P<0.05) in the 400 and 800 p.p.m. of ONO-8711, respectively. The multiplicity of tongue cancer was also smaller in the 4-NQO + ONO-8711 (400 p.p.m. ONO-8711, 0.35 +/- 0.61; and 800 p.p.m. ONO-8711, 0.29 +/- 0.47; P<0.05), when compared with the 4-NQO alone group (0.88 +/- 0.88). Feeding with ONO-8711 significantly reduced PGE(2) level and cell proliferation activity in the non-tumorous epithelium of the tongue. Also, treatment with ONO-8711 resulted in the decrease in EP(1) immunohistochemical expression in the tongue lesions induced by 4-NQO. The results suggest that EP(1) receptor involves in oral carcinogenesis, and that an EP1-selective antagonist ONO-8711 exerts the cancer chemopreventive effects through the suppression of EP(1) expression, PGE(2) biosynthesis and cell proliferation.
Makita
Hiroki
H
Department of Oral and Maxillofacial Sciences, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan.
Mutoh
Michihiro
M
Maruyama
Takayuki
T
Yonemoto
Kazuhiro
K
Kobayashi
Atsushi
A
Fujitsuka
Hideki
H
Toida
Makoto
M
Shibata
Toshiyuki
T
Miyamoto
Shingo
S
Yasui
Yumiko
Y
Suzuki
Rikako
R
Wakabayashi
Keiji
K
Tanaka
Takuji
T
D015112:4-Nitroquinoline-1-oxide / Q000633:toxicity*; D000821:Animal Feed; D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D002208:Caproates / Q000494:pharmacology*; D002273:Carcinogens / Q000633:toxicity; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D015232:Dinoprostone / Q000378:metabolism; D008297:Male; D011230:Precancerous Conditions / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D051381:Rats; D011916:Rats, Inbred F344; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors*; D014059:Tongue / Q000378:metabolism; D014062:Tongue Neoplasms / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control*
D001643:Bridged Bicyclo Compounds; D002208:Caproates; D002273:Carcinogens; C122148:ONO 8711; D018078:Receptors, Prostaglandin E; D015112:4-Nitroquinoline-1-oxide; D015232:Dinoprostone