Effectiveness of IkappaB kinase inhibitors in murine colitis-associated tumorigenesis.
OBJECTIVE
Nuclear factor kappaB (NF-kappaB) 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 IKKbeta, which is a critical kinase for NF-kappaB 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 IKKbeta inhibitors, NBD peptide, and IMD-0354 were examined.


RESULTS
In a colitis-associated cancer model, treatment with the IKKbeta 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-kappaB activation and the expression of Cox-2 and iNOS were observed in tumor tissues, and the inhibitors ameliorated their expression. These inhibitors blocked NF-kappaB 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.


CONCLUSIONS
These results imply that IKKbeta-targeted NF-kappaB blockade is an attractive therapeutic approach for the prevention of colitis-associated tumors.
Hayakawa
Yoku
Y
Department of Gastroenterology, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
Maeda
Shin
S
Nakagawa
Hayato
H
Hikiba
Yohko
Y
Shibata
Wataru
W
Sakamoto
Kei
K
Yanai
Ayako
A
Hirata
Yoshihiro
Y
Ogura
Keiji
K
Muto
Susumu
S
Itai
Akiko
A
Omata
Masao
M
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001397:Azoxymethane / Q000633:toxicity; D001549:Benzamides / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D003092:Colitis / Q000150:complications / Q000473:pathology; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D016264:Dextran Sulfate / Q000633:toxicity; D016503:Drug Delivery Systems; D004354:Drug Screening Assays, Antitumor; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D020556:Neutrophil Infiltration / Q000187:drug effects; D010455:Peptides / Q000494:pharmacology*
D000970:Antineoplastic Agents; D001549:Benzamides; C467063:NBD peptide, mouse; D016328:NF-kappa B; D010455:Peptides; C492919:N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2-hydroxybenzamide; D016264:Dextran Sulfate; D051550:I-kappa B Kinase; D001397:Azoxymethane