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Carcinogenesis Advance Access originally published online on October 19, 2006
Carcinogenesis 2007 28(3):677-684; doi:10.1093/carcin/bgl178
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

A prostaglandin E2 receptor subtype EP1-selective antagonist, ONO-8711, suppresses 4-nitroquinoline 1-oxide-induced rat tongue carcinogenesis

Hiroki Makita1, Michihiro Mutoh2, Takayuki Maruyama3, Kazuhiro Yonemoto1, Atsushi Kobayashi1, Hideki Fujitsuka1, Makoto Toida1, Toshiyuki Shibata1, Shingo Miyamoto4,5, Yumiko Yasui4, Rikako Suzuki4, Keiji Wakabayashi2 and Takuji Tanaka4,*

1 Department of Oral and Maxillofacial Sciences, Gifu University Graduate School of Medicine 1-1 Yanagido, Gifu 501-1194, Japan
2 Cancer Prevention Basic Research Project, National Cancer Center Research Institute 1-1 Tsukiji, 5-chome, Chuo-ku, Tokyo 104-0045, Japan
3 Minase Research Institute, One Pharmaceutical Company Limited 3-1-1 Sakurai, Shimamoto-cho, Mishima-gunn, Osaka 618-8585, Japan
4 Department of Oncologic Pathology, Kanazawa Medical University 1-1 Daigaku, Uchinada, Ishikawa 920-0293, Japan
5 Division of Food Science and Biotechnology, Graduate School of Agriculture Kyoto University, Kyoto 606-8502, Japan

*To whom correspondence and requests for reprint should be addressed. Tel: +81 76 286 2211 (ext. 3611); Fax: +81 76 286 6926; Email: takutt{at}kanazawaa-med.ac.jp

We previously reported that certain cyclooxygenase (COX) inhibitors could inhibit chemically induced tongue carcinogenesis. In the present study, we investigated the effects of prostaglandin E2 (PGE2) receptor EP1-selective antagonist ONO-8711 on 4-nitroquinoline 1-oxide (4-NQO)-induced oral carcinogenesis to know whether an EP1 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 PGE2 level and cell proliferation activity in the non-tumorous epithelium of the tongue. Also, treatment with ONO-8711 resulted in the decrease in EP1 immunohistochemical expression in the tongue lesions induced by 4-NQO. The results suggest that EP1 receptor involves in oral carcinogenesis, and that an EP1-selective antagonist ONO-8711 exerts the cancer chemopreventive effects through the suppression of EP1 expression, PGE2 biosynthesis and cell proliferation.

Abbreviations: AOM, azoxymethane; BrdU, 5-bromodeoxyuridine; COX, cyclooxygenase; 4-NQO, 4-nitroquinoline 1-oxide; NSAIDs, non-steroidal anti-inflammatory drugs; ONO-8711, 6-[(2S,3S)-3-(4-chloro-2-methylphenylsulfonyl-amnomethyl)-bicyclo[2.2.2.] octan-2-yl]-5Z-hexenoic acid; PAP, squamous cell papilloma; PGE2, prostaglandin E2; SCC, squamous cell carcinoma.

Received July 12, 2006; revised August 25, 2006; accepted September 11, 2006.


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