Patients with inflammatory bowel disease (IBD) develop malignancies of the intestinal tract at an increased frequency compared to the normal population. This is thought to be due, in part, to the chronic inflammation associated with this debilitating disease. Cyclosporine A (CsA) is an effective treatment for patients with severe, steroid-refractory IBD, especially ulcerative colitis (UC). However, the use of CsA in animal models has been associated with enhanced spread of colorectal cancer cells. We have shown that treatment of bone marrow transplanted (BMT) mice with CsA leads to a colitis-like disease similar to other models of IBD. Importantly, recent studies have demonstrated a role for the inflammasome, in intestinal homeostasis and the development of colitis-associated intestinal tumors. IBD patients have decreased inflammasome activity which may contribute to the development of clinical disease and animals with deficiencies in the inflammasome develop enhanced colitis and colon tumors. We have documented that CsA-treatment of BMT mice inhibited the activation of the inflammasome and may have participated in the development of colitis-like disease, making suspect the clinical use of CsA in refractory IBD. Given these findings two specific aims will be proposed to test the hypothesis that cyclosporine treatment will alter intestinal homeostasis via inhibition of inflammasome function, resulting in enhanced tumor growth in the azoxymethane (AOM)/dextran sulfate sodium (DSS) model of colitis-associated colon cancer (CAC).
Aim 1 will determine if treatment of AOM/DSS- treated animals with a therapeutic dose of CsA will enhance the severity of colitis and the development of CAC. Inflammasome expression and activity will be determined in CsA-treated mice after induction of AOM/DSS CAC. Preliminary results show that CsA therapy inhibits intestinal barrier function in BMT mice. Thus, we propose that intestinal damage which occurs during the induction of AOM/DSS also will be prolonged by CsA therapy.
Aim 2 will test the hypothesis that CsA-induced alterations in intestinal epithelium will lead to increased permeability and decreased barrier function via inhibition of inflammasome function, which may contribute to increased colitis and development of CAC. As patients with IBD have reduced inflammasome activity, the potential exists that the use of CsA to treat refractory IBD may enhance development of the disease by further reducing inflammasome function, leading to and enhanced risk of CAC. It is imperative to analyze the effects of immunosuppressive therapy on intestinal damage, induction of colitis and CAC in model animal systems to understand the risk of CsA therapy in the treatment of IBD.

Public Health Relevance

The murine AOM/DSS model exhibits many of the characteristics of IBD-associated colon cancer and is useful as a proof of concept model to examine the role of calcineurin inhibition in the integrity of the intestinal epithelium during chronic inflammation. This project will determine the effect of CsA/immunosuppressive therapy on the development of inducible colon cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Small Research Grants (R03)
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Special Emphasis Panel (ZCA1-RTRB-Z (O1))
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Daschner, Phillip J
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University of Kentucky
Internal Medicine/Medicine
Schools of Medicine
United States
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