Patients with inflammatory bowel disease (IBD) have a 20 to 30-fold increased risk of colorectal cancer relative to the general population. This increased cancer risk has been attributed to genetic damage from oxidative stress caused by inflammatory mediators combined with the proliferation of colonic epithelium during mucosal repair. IBD-associated neoplasia can be detected at an early, potentially curable stage by colonoscopic screening. However, safe and effective new strategies for preventing colon cancer would be of great benefit to IBD patients and should ultimately lead to considerable cost savings. Recent animal studies have shown that inhibiting T cell-mediated colon inflammation can decrease the risk of colon cancer. Our studies show that oral administration of bromelain, a proteinase mixture derived from pineapple, significantly decreases both the incidence of spontaneous colitis and the severity of established T cell-mediated colitis in IL-10-deficient mice. Previous in vitro studies by our laboratory and others have shown that bromelain decreases T cell proliferation, signal transduction, and cytokine production. Its anti-inflammatory effects in vitro and in vivo depend on its proteolytic activity. This proposal is designed to test the hypothesis that bromelain treatment will decrease the risk of IBD-associated colon cancer by decreasing the genetic damage caused by T cell-mediated inflammation.
The specific aims will determine the effect of bromelain on inflammation and development of colon neoplasia in mice with chronic T cell-mediated colitis. The severity of inflammation and the incidence of colonic neoplasia will be determined histologically. Inflammation-associated oxidative lesions in DNA and treatment-related effects on signal transduction and critical biomarker expression will be determined to directly assess effects of bromelain on pathways critical to inflammation and colorectal carcinogenesis. The proposed studies will further elucidate mechanisms that can lead to novel interventions to prevent IBD-associated colon cancers, providing great benefit to IBD patients and their families. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA115480-03
Application #
7496973
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Kim, Young S
Project Start
2006-09-29
Project End
2011-07-31
Budget Start
2008-08-01
Budget End
2009-07-31
Support Year
3
Fiscal Year
2008
Total Cost
$241,983
Indirect Cost
Name
Duke University
Department
Pathology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
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Hampton, Daniel D; Hale, Laura P (2011) Mast cells are critical for protection against peptic ulcers induced by the NSAID piroxicam. PLoS One 6:e23669
Chichlowski, Maciej; Westwood, Greg S; Abraham, Soman N et al. (2010) Role of mast cells in inflammatory bowel disease and inflammation-associated colorectal neoplasia in IL-10-deficient mice. PLoS One 5:e12220
Vanderford, Deborah A; Greer, Paula K; Sharp, Julie M et al. (2010) Alopecia in IL-10-deficient mouse pups is c-kit-dependent and can be triggered by iron deficiency. Exp Dermatol 19:518-26
Hale, Laura P; Chichlowski, Maciej; Trinh, Chau T et al. (2010) Dietary supplementation with fresh pineapple juice decreases inflammation and colonic neoplasia in IL-10-deficient mice with colitis. Inflamm Bowel Dis 16:2012-21
Chichlowski, Maciej; Hale, Laura P (2009) Effects of Helicobacter infection on research: the case for eradication of Helicobacter from rodent research colonies. Comp Med 59:10-7
Sharp, Julie M; Vanderford, Deborah A; Chichlowski, Maciej et al. (2008) Helicobacter infection decreases reproductive performance of IL10-deficient mice. Comp Med 58:447-53
Chichlowski, Maciej; Hale, Laura P (2008) Bacterial-mucosal interactions in inflammatory bowel disease: an alliance gone bad. Am J Physiol Gastrointest Liver Physiol 295:G1139-49
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Hale, Laura P; Perera, Dinushi; Gottfried, Marcia R et al. (2007) Neonatal co-infection with helicobacter species markedly accelerates the development of inflammation-associated colonic neoplasia in IL-10(-/-) mice. Helicobacter 12:598-604