Approximately one million people worldwide will die of colon cancer this coming year. Since the survival of patients with metastatic colon cancer is poor, chemoprevention has become increasingly important as a strategy to reduce the incidence and progression of pre-neoplastic alterations that lead to cancer. The majority of sporadic colon cancers are associated with a high-fat/low vegetable diet (Western-style diet). Hydrophobic bile acids [i.e. deoxycholic acid (DOC)] are increased in the gut of patients on a Western-style diet and can cause oxidative DNA damage. The hypothesis to be tested is: the prevention of DOC-induced oxidative/nitrosative stress will reduce nuclear and mitochondrial DNA (mtDNA) damage and decrease colon tumorigenesis. We will use hypothesis-driven, non-toxic chemopreventive agents that interfere with the deleterious effects of DOC and include parthenolide, an NF-=B inhibitor, organic selenium compounds, chlorogenic acid and novel antioxidants that target mitochondria (e.g. MitoQ-ubiquinol). This proposal has 3 specific aims that will determine the: 1) capability of hypothesis-driven chemopreventive agents to reduce DOC-induced nuclear and mtDNA damage in vivo using mouse models, 2) role of the natural antioxidant, chlorogenic acid, on the modulation of oxidative stress-related DNA repair proteins in vivo using wild-type and genetically-modified mice in the presence and absence of DOC, and 3) effectiveness of chemopreventive agents in decreasing colon tumorigenesis in the presence and absence of the tumor promoter, DOC. We will be using molecular and cellular techniques on mouse colon to assess oxidized and nitrated bases in nuclear DNA and will assess mitochondrial DNA damage using semiquantitative PCR. This project will utilize four distinct animal models: 1) DOC-induced nitrosative stress mouse model (wild-type B6.129 mice) developed in our laboratory; 2) NOS-/- k.o./DOC mouse model; 3) arginine-enhanced colon tumor ApcMin/+ mouse model developed in our laboratory; 4) the AOM mouse model of colon carcinogenesis using A/J mice. ? ? ?

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Chemo/Dietary Prevention Study Section (CDP)
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Perloff, Marjorie
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University of Arizona
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Payne, Claire M; Crowley-Skillicorn, Cheray; Bernstein, Carol et al. (2010) Hydrophobic bile acid-induced micronuclei formation, mitotic perturbations, and decreases in spindle checkpoint proteins: relevance to genomic instability in colon carcinogenesis. Nutr Cancer 62:825-40
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Payne, C M; Weber, C; Crowley-Skillicorn, C et al. (2007) Deoxycholate induces mitochondrial oxidative stress and activates NF-kappaB through multiple mechanisms in HCT-116 colon epithelial cells. Carcinogenesis 28:215-22