A specific inducible nitric oxide synthase inhibitor, ONO-1714 attenuates inflammation-related large bowel carcinogenesis in male Apc(Min/+) mice

• Published in: International journal of cancer 2007-08, Vol.121 (3), p.506
• Main Authors: Kohno, Hiroyuki, Takahashi, Mami, Yasui, Yumiko, Suzuki, Rikako, Miyamoto, Shingo, Kamanaka, Yoshihisa, Naka, Masao, Maruyama, Takayuki, Wakabayashi, Keiji, Tanaka, Takuji
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - prevention & control; Adenomatous Polyposis Coli - genetics; Amidines - administration & dosage; Amidines - pharmacology; Animals; Colitis - chemically induced; Colitis - complications; Colonic Neoplasms - prevention & control; Cyclooxygenase 2 - metabolism; Dextran Sulfate; Dose-Response Relationship, Drug; Heterocyclic Compounds, 2-Ring - administration & dosage; Heterocyclic Compounds, 2-Ring - pharmacology; Interleukin-1beta - metabolism; Intestinal Mucosa - metabolism; Male; Mice; Mice, Inbred C57BL; Nitric Oxide Synthase Type II - antagonists & inhibitors; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - analysis; Triglycerides - blood; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0020-7136
• DOI: 10.1002/ijc.22736

It is generally assumed that inflammation influences carcinogenesis. We previously reported that dextran sodium sulfate (DSS) strongly enhances colon carcinogenesis in the Apc(Min/+) mice and the over-expression of inducible nitric oxide synthase (iNOS) contributes to this enhancement. In the current study, we investigated the effect of a selective iNOS inhibitor, ONO-1714 on colitis-related colon carcinogenesis in the Apc(Min/+) mouse treated with DSS. Male C57BL/6J Apc(Min/+) and Apc(+/+) mice were exposed to 1% DSS in their drinking water for 7 days. ONO-1714 was given to the mice at a dose level of 50 or 100 ppm in diet for 5 weeks (during the administration of DSS). The tumor inhibitory effects by ONO-1714 were assessed at week 5 by counting the incidence and multiplicity of colonic neoplasms. Additionally, we assessed serum lipid levels and colonic mRNA expression for cyclooxygenase (COX)-2, iNOS, tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta. Feeding with ONO-1714 significantly inhibited the occurrence of colonic adenocarcinoma in a dose-dependent manner in the Apc(Min/+) mice. In addition, the treatment with ONO-1714 significantly lowered the serum triglyceride levels and mRNA expression levels of COX-2, TNFalpha and IL-1beta of colonic mucosa in the DSS-treated Apc(Min/+) mice. Neither ONO-1714 nor DSS affected the colonic pathology in the Apc(+/+) mice. Our findings may suggest that ONO-1714 could therefore serve as an effective agent for suppression of colitis-related colon cancer development in the Apc(Min/+) mice.