Carcinogenesis Advance Access published online on October 19, 2006
Carcinogenesis, doi:10.1093/carcin/bgl178
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1 Department of Oral and Maxillofacial Sciences, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan
* To whom correspondence should be addressed. We previously reported that certain cyclooxygenase 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 ppm for the initial 2 weeks, 25 ppm for 2 weeks, and then 30 ppm for 4 weeks). After 4-NQO treatment, animals were given 400 or 800 ppm ONO-8711 containing diets for 23 weeks. The incidence of tongue squamous cell carcinomas 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 ppm of ONO-8711, respectively. The multiplicity of tongue cancer was also smaller in the 4-NQO + ONO-8711 (400 ppm ONO-8711, 0.35±0.61, and 800 ppm ONO-8711, 0.29±0.47, P<0.05), when compared to 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-selsctive antagonist ONO-8711 exerts the cancer chemopreventive effects through the suppression of EP1 expression, PGE2 biosynthesis, and cell proliferation.
Received July 12, 2006
Revised August 25, 2006
Accepted September 11, 2006
CANCER PREVENTION
A prostaglandin E2 receptor subtype EP1-selective antagonist, ONO-8711, suppresses 4-nitroquinoline 1-oxide-induced rat tongue carcinogenesis
Hiroki Makita 1, Michihiro Mutoh 2, Takayuki Maruyama 3, Kazuhiro Yonemoto 1, Atsushi Kobayashi 1, Hideki Fujitsuka 1, Makoto Toida 1, Toshiyuki Shibata 1, Shingo Miyamoto 4, Yumiko Yasui 5, Rikako Suzuki 5, Keiji Wakabayashi 2, and Takuji Tanaka 5 *
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 Co., Ltd., 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; Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan
5 Department of Oncologic Pathology, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Ishikawa 920-0293, Japan
Takuji Tanaka, E-mail: takutt{at}kanazawaa-med.ac.jp
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