Colorectal cancer is the fifth most common cancer in the United States and the third leading cause of cancer-related death in the developed countries. Colonic inflammation (colitis), particularly inflammatory bowel disease (IBD), is strongly associated with the development of colon cancer. Therefore, the treatment or prevention of colitis is critical to colon cancer prevention. We have already identified a novel peptide that in preliminary experiments showed a strong suppressive effect on colonic inflammation in chemical-induced colitis animal models. In this proposal, we will further confirm and refine the inhibitory effect of the peptide in dextran sulfate sodium (DSS)-induced acute colitis mouse model. The mechanism by which this peptide suppresses colitis will also be explored. Based on our preliminary results, the inhibition of over-activated NF-?B may be the key. We will focus on identifying the effect of the peptide along the NF-?B signaling pathway, with particular emphasis on examining the phosphorylation of NF-?B, I-?B, and IKK. Furthermore, we propose to study the ability of the peptide to prevent colon cancer. An AOM/DSS-induced colitis-associated colon cancer animal model is well-established for this purpose. As previous studies showed, a low dose of AOM alone cannot induce colon tumors but the same dose of AOM plus DSS exposure can induce a 100% incidence of colon tumors. We propose that the peptide has potential as a preventive agent against colon cancer because of its prominent suppressive effect on DSS-induced colitis.
In this proposal, we will test the effect of a novel peptide, QAW, in its suppression of colonic inflammation. Subsequently, we will examine its inhibitory effect on the development of colon cancer in a mice model. This peptide is derived from a well-known anti-inflammatory protein, Annexin A1 and, in our preliminary animal studies, has shown an anti-inflammatory effect. Due to the fact that colitis plays an important role in the development of colitis-associated colon cancer, we propose that QAW can prevent colon cancer via its anti-inflammatory effect. To test this effect of QAW, we will induce colitis and colon cancer in animal models using dextran sulfate sodium (DSS) and azoxymethane (AOM)/DSS. These models mimic human inflammatory bowel disease (IBD) and colitis related colon cancer. The inhibitory effect of QAW on NF-?B over-activation, which is a master regulator in inflammation, has been preliminarily observed in vitro and in vivo. In addition, we will also instigate a detailed study relating to this mechanism.
| Ouyang, Nengtai; Zhu, Caihua; Zhou, Dingying et al. (2012) MC-12, an annexin A1-based peptide, is effective in the treatment of experimental colitis. PLoS One 7:e41585 |
