Effectiveness of IκB kinase inhibitors in murine colitis-associated tumorigenesis

Abstract

PurposeNuclear 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.

MethodsWe 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.

ResultsIn 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.

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