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Effectiveness of IκB kinase inhibitors in murine colitis-associated tumorigenesis

  • Original Article—Alimentary Tract
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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.

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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

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Acknowledgments

This study was supported by Grants-in-Aid (#17209026 and #18890244) from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

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Authors and Affiliations

  1. Department of Gastroenterology, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan

    Yoku Hayakawa, Shin Maeda, Hayato Nakagawa, Wataru Shibata, Kei Sakamoto, Yoshihiro Hirata, Keiji Ogura & Masao Omata

  2. Division of Gastroenterology, Institute for Adult Diseases, Asahi Life Foundation, 1-6-1 Marunouchi, Chiyoda-ku, Tokyo, 100-0005, Japan

    Shin Maeda, Yohko Hikiba, Kei Sakamoto & Ayako Yanai

  3. Institute of Medicinal Molecular Design, Inc, 5-24-5 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan

    Susumu Muto & Akiko Itai

Authors
  1. Yoku Hayakawa
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  2. Shin Maeda
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  3. Hayato Nakagawa
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  4. Yohko Hikiba
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  5. Wataru Shibata
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  6. Kei Sakamoto
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  7. Ayako Yanai
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  8. Yoshihiro Hirata
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  9. Keiji Ogura
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  10. Susumu Muto
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  11. Akiko Itai
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  12. Masao Omata
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Corresponding author

Correspondence to Shin Maeda.

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Hayakawa, Y., Maeda, S., Nakagawa, H. et al. Effectiveness of IκB kinase inhibitors in murine colitis-associated tumorigenesis. J Gastroenterol 44, 935–943 (2009). https://doi.org/10.1007/s00535-009-0098-7

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  • DOI: https://doi.org/10.1007/s00535-009-0098-7

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