Journal of Gastroenterology

, Volume 44, Issue 9, pp 935–943

Effectiveness of IκB kinase inhibitors in murine colitis-associated tumorigenesis

  • Yoku Hayakawa
  • Shin Maeda
  • Hayato Nakagawa
  • Yohko Hikiba
  • Wataru Shibata
  • Kei Sakamoto
  • Ayako Yanai
  • Yoshihiro Hirata
  • Keiji Ogura
  • Susumu Muto
  • Akiko Itai
  • Masao Omata
Original Article—Alimentary Tract

DOI: 10.1007/s00535-009-0098-7

Cite this article as:
Hayakawa, Y., Maeda, S., Nakagawa, H. et al. J Gastroenterol (2009) 44: 935. doi:10.1007/s00535-009-0098-7

Abstract

Purpose

Nuclear factor κB (NF-κB) activation is involved in various inflammatory illnesses, for example inflammatory bowel disease, and is thought to be a key factor in the tumor-promoting mechanism of inflammation-associated tumorigenesis. This study investigated whether inhibitors of IKKβ, which is a critical kinase for NF-κB activation, reduce colitis-associated tumorigenesis in mice.

Methods

We used a mouse model of the disease whereby administration of azoxymethane (AOM) followed by repeated dextran sulfate sodium (DSS) ingestion causes severe colonic inflammation and the subsequent development of multiple tumors. Effects of IKKβ inhibitors, NBD peptide, and IMD-0354 were examined.

Results

In a colitis-associated cancer model, treatment with the IKKβ inhibitors NBD peptide and IMD-0354 significantly reduced the number of tumors compared with the untreated group. The tumors were also significantly smaller in the inhibitor-treated mice than in the untreated mice. Macrophage and neutrophil infiltration decreased with the inhibitor treatment. NF-κB activation and the expression of Cox-2 and iNOS were observed in tumor tissues, and the inhibitors ameliorated their expression. These inhibitors blocked NF-κB activation and the expression of proinflammatory cytokines mediated by the culture supernatant of inflamed colon in murine primary macrophages. In-vitro and in-vivo experiments showed that these drugs, especially NBD peptide, could also inhibit the proliferation of colonic epithelial cells.

Conclusion

These results imply that IKKβ-targeted NF-κB blockade is an attractive therapeutic approach for the prevention of colitis-associated tumors.

Keywords

Inflammatory bowel disease (IBD)TumorNF-κBCytokine

Abbreviations

NF-κB

Nuclear factor kappa B

IKK

I kappa B kinase

CRC

Colorectal cancer

CAC

Colitis-associated cancer

DSS

Dextran sulfate sodium salt

TNF

Tumor necrosis factor

IL

Interleukin

IBD

Inflammatory bowel disease

Copyright information

© Springer 2009

Authors and Affiliations

  • Yoku Hayakawa
    • 1
  • Shin Maeda
    • 1
    • 2
  • Hayato Nakagawa
    • 1
  • Yohko Hikiba
    • 2
  • Wataru Shibata
    • 1
  • Kei Sakamoto
    • 1
    • 2
  • Ayako Yanai
    • 2
  • Yoshihiro Hirata
    • 1
  • Keiji Ogura
    • 1
  • Susumu Muto
    • 3
  • Akiko Itai
    • 3
  • Masao Omata
    • 1
  1. 1.Department of GastroenterologyUniversity of TokyoTokyoJapan
  2. 2.Division of GastroenterologyInstitute for Adult Diseases, Asahi Life FoundationTokyoJapan
  3. 3.Institute of Medicinal Molecular Design, IncTokyoJapan