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Carcinogenesis Advance Access published online on January 23, 2004
Carcinogenesis, doi:10.1093/carcin/bgh093
© 2004 by Oxford University Press
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© 2004 Oxford University Press

MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION

An acyclic retinoid, NIK-333, inhibits N-diethylnitrosamine-induced rat hepatocarcinogenesis through suppression of TGF-{alpha} expression and cell proliferation

Masataka Kagawa 1, Tetsuro Sano 1, Naoto Ishibashi 1, Manabu Hashimoto 1, Masataka Okuno 2, Hisataka Moriwaki 2, Rikako Suzuki 3, Hiroyuki Kohno 3, and Takuji Tanaka 3*

1 Pharmaceutical Research Laboratories, Nikken Chemicals Co. Ltd, 1-346 Kitabukuro-cho, Omiya-ku, Saitama-shi, Saitama 330-0835
2 The First Department of Internal Medicine, Gifu University School of Medicine, 40 Tsukasa-machi, Gifu 550-8705
3 The First Department of Pathology, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Ishikawa 920-0293, Japan

* Corresponding author. E-mail: takutt{at}kanazawa-med.ac.jp.

Received 1 November 2003 ; revised 12 January 2004 ; accepted 14 January 2004

Abstract

The present study was designed to determine the effects of NIK-333, a synthetic acyclic retinoid, on N-nitrosodiethylamine (DEN)-induced hepatocarcinogenesis in male F344 rats. Animals were given DEN dissolved in drinking water at a concentration of 40 ppm for 5 weeks and then provided with drinking water free of DEN for 15 weeks to induce hepatocellular neoplasms. NIK-333 was administered orally (once a day) to rats at doses of 10, 40 and 80 mg/kg body weight for 14 weeks, starting one week after the completion of administration of DEN. At 20 weeks after the start of DEN administration, histopathological evaluation was carried out on all animals. The effects of NIK-333 on the cell proliferative activity of non-tumorous area and liver tumor cells and the immunohistochemical expression of transforming growth factor (TGF)-{alpha} were also evaluated. NIK-333 at 40 and 80 mg/kg body weight significantly inhibited hepatocarcinogenesis (p<0.05). In addition, NIK-333 at the same doses decreased DEN-induced overexpression of TGF-{alpha} in hepatocellular neoplasms (adenomas and carcinomas) and their surrounding tissue. Furthermore, NIK-333 significantly inhibited the cell proliferation activity in the lesions and non-tumorous areas (p<0.01). Our results suggest that NIK-333 inhibits DEN-induced hepatocarcinogenesis through suppression of TGF-{alpha} expression and cell proliferation.

hepatocarcinogenesis, transforming growth factor-alfa, acyclic retinoids, rat
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