title: A prostaglandin E2 receptor subtype EP1-selective antagonist, ONO-8711, suppresses 4-nitroquinoline 1-oxide-induced rat tongue carcinogenesis.
abstract: 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.
authors.affiliation: Department of Oral and Maxillofacial Sciences, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Makita
authors.forename: Michihiro
authors.initials: M
authors.lastname: Mutoh
authors.forename: Takayuki
authors.initials: T
authors.lastname: Maruyama
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Yonemoto
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kobayashi
authors.forename: Hideki
authors.initials: H
authors.lastname: Fujitsuka
authors.forename: Makoto
authors.initials: M
authors.lastname: Toida
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Shibata
authors.forename: Shingo
authors.initials: S
authors.lastname: Miyamoto
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Yasui
authors.forename: Rikako
authors.initials: R
authors.lastname: Suzuki
authors.forename: Keiji
authors.initials: K
authors.lastname: Wakabayashi
authors.forename: Takuji
authors.initials: T
authors.lastname: Tanaka
mesh_terms: 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*
chemical_list: D001643:Bridged Bicyclo Compounds; D002208:Caproates; D002273:Carcinogens; C122148:ONO 8711; D018078:Receptors, Prostaglandin E; D015112:4-Nitroquinoline-1-oxide; D015232:Dinoprostone