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: Masataka Kagawa, Tetsuro Sano, Naoto Ishibashi, Manabu Hashimoto, Masataka Okuno, Hisataka Moriwaki, Rikako Suzuki, Hiroyuki Kohno, Takuji Tanaka
• Journal: Carcinogenesis (Carcinogenesis) Vol. 25 Issue 6 Pg. 979-85 (Jun 2004) ISSN: 0143-3334 [Print] England
• PMID: 14742314 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anticarcinogenic Agents
• Retinoids
• Transforming Growth Factor alpha
• (2E,4E,6E,10E)-3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid
• Diethylnitrosamine

Topics

• Animals
• Anticarcinogenic Agents (pharmacology)
• Cell Division (drug effects)
• Diethylnitrosamine (toxicity)
• Dose-Response Relationship, Drug
• Immunohistochemistry
• Liver Neoplasms, Experimental (chemically induced, metabolism, pathology, prevention & control)
• Male
• Rats
• Rats, Inbred F344
• Retinoids (pharmacology)
• Transforming Growth Factor alpha (antagonists & inhibitors, metabolism)