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

Abstract

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.

• Authors: Hiroyuki Kohno, Mami Takahashi, Yumiko Yasui, Rikako Suzuki, Shingo Miyamoto, Yoshihisa Kamanaka, Masao Naka, Takayuki Maruyama, Keiji Wakabayashi, Takuji Tanaka
• Journal: International journal of cancer (Int J Cancer) Vol. 121 Issue 3 Pg. 506-13 (Aug 01 2007) ISSN: 0020-7136 [Print] United States
• PMID: 17417780 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright (c) 2007 Wiley-Liss, Inc.

Chemical References

• 7-chloro-3-imino-5-methyl-2-azabicyclo(4.1.0)heptane
• Amidines
• Heterocyclic Compounds, 2-Ring
• Interleukin-1beta
• RNA, Messenger
• Triglycerides
• Tumor Necrosis Factor-alpha
• Dextran Sulfate
• Nitric Oxide Synthase Type II
• Ptgs2 protein, mouse
• Cyclooxygenase 2

Topics

• Adenocarcinoma (prevention & control)
• Adenomatous Polyposis Coli (genetics)
• Amidines (administration & dosage, pharmacology)
• Animals
• Colitis (chemically induced, complications)
• Colonic Neoplasms (prevention & control)
• Cyclooxygenase 2 (metabolism)
• Dextran Sulfate
• Dose-Response Relationship, Drug
• Heterocyclic Compounds, 2-Ring (administration & dosage, pharmacology)
• Interleukin-1beta (metabolism)
• Intestinal Mucosa (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Nitric Oxide Synthase Type II (antagonists & inhibitors)
• RNA, Messenger (analysis)
• Reverse Transcriptase Polymerase Chain Reaction
• Triglycerides (blood)
• Tumor Necrosis Factor-alpha (metabolism)