Department of Gastroenterology, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
J Gastroenterol. 2009;44(9):935-43. doi: 10.1007/s00535-009-0098-7. Epub 2009 Jun 26.
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.
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.
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.
These results imply that IKKbeta-targeted NF-kappaB blockade is an attractive therapeutic approach for the prevention of colitis-associated tumors.
核因子 kappaB（NF-κB）的激活与多种炎症性疾病有关，例如炎症性肠病，并且被认为是炎症相关肿瘤发生中促进肿瘤的机制中的关键因素。本研究探讨了 IKKβ抑制剂是否可以减少小鼠的结肠炎相关肿瘤形成，IKKβ是 NF-κB 激活的关键激酶。
我们使用了一种疾病小鼠模型，其中给予氧化偶氮甲烷（AOM）后再重复给予葡聚糖硫酸钠（DSS）会导致严重的结肠炎症和随后的多发性肿瘤形成。研究了 IKKβ抑制剂 NBD 肽和 IMD-0354 的作用。
在结肠炎相关的癌症模型中，与未治疗组相比，用 IKKβ抑制剂 NBD 肽和 IMD-0354 治疗可显著减少肿瘤数量。与未治疗组相比，抑制剂治疗组的肿瘤也明显更小。抑制剂治疗可减少巨噬细胞和中性粒细胞浸润。在肿瘤组织中观察到 NF-κB 激活以及 Cox-2 和 iNOS 的表达，并且抑制剂改善了它们的表达。这些抑制剂可阻断 NF-κB 激活以及由发炎结肠的培养上清液介导的促炎细胞因子的表达。在体外和体内实验中，这些药物，特别是 NBD 肽，也可以抑制结肠上皮细胞的增殖。
这些结果表明，针对 IKKβ的 NF-κB 阻断是预防结肠炎相关肿瘤的一种有吸引力的治疗方法。
