title: An acyclic retinoid, NIK-333, inhibits N-diethylnitrosamine-induced rat hepatocarcinogenesis through suppression of TGF-alpha expression and cell proliferation.
abstract: The present study was designed to determine the effects of NIK-333, a synthetic acyclic retinoid, on N-diethylnitrosamine (DEN)-induced hepatocarcinogenesis in male F344 rats. Animals were given DEN dissolved in drinking water at a concentration of 40 p.p.m. 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 wt for 14 weeks, starting 1 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 proliferation activity of non-tumorous areas and liver tumor cells and the immunohistochemical expression of transforming growth factor-alpha (TGF-alpha) were also evaluated. NIK-333 at 40 and 80 mg/kg body wt 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 cell proliferation activity in the lesions and in 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.
authors.affiliation: Pharmaceutical Research Laboratories, Nikken Chemicals Co. Ltd, 1-346 Kitabukuro-cho, Omiya-ku, Saitama-shi, Saitama 330-0835, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Kagawa
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Sano
authors.forename: Naoto
authors.initials: N
authors.lastname: Ishibashi
authors.forename: Manabu
authors.initials: M
authors.lastname: Hashimoto
authors.forename: Masataka
authors.initials: M
authors.lastname: Okuno
authors.forename: Hisataka
authors.initials: H
authors.lastname: Moriwaki
authors.forename: Rikako
authors.initials: R
authors.lastname: Suzuki
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kohno
authors.forename: Takuji
authors.initials: T
authors.lastname: Tanaka
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects*; D004052:Diethylnitrosamine / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D007150:Immunohistochemistry; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D012176:Retinoids / Q000494:pharmacology*; D016211:Transforming Growth Factor alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D016588:Anticarcinogenic Agents; D012176:Retinoids; D016211:Transforming Growth Factor alpha; C487689:(2E,4E,6E,10E)-3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid; D004052:Diethylnitrosamine