The overarching goal for this project is to provide an efficient agent for the prevention of colitis-induced cancer. Chronic colitis is a well-recognized risk factor of colon cancer;an increase in colitis-induced aberrant arachidonic acid (AA) metabolites is a key event leading to cancer development. Epoxyeicosatrienoic acids (EETs) are AA metabolites with anti-inflammatory activity;under physiological conditions, EETs are quickly inactivated as they are converted to their corresponding dihydroxyeicosatrienoic acids (DHETs) by the enzyme soluble epoxide hydrolase (sEH) (1, 2). The inhibition of sEH prevents the complete hydrolysis of the epoxide, reducing the conversion of EETs to DHETs. Our preliminary studies have shown that 1) sEH inhibitors AUDA- nBE and t-AUCB significantly inhibit colitis and ulcer formation by suppressed macrophage/neutrophile activity as well as decreased iNOS expression and its mediated nitrotyrosine formation. 2) AUDA-nBE induced PPAR- gamma activity and inhibited NF-kB signaling. iNOS, COX2, 5-LOX, nitro-oxidative stress and VCAM-1 was also inhibited in vitro cell lines (15). 3) Long-term administration of t-AUCB inhibited development of colitis- induced dysplasia and carcinoma in rodent models. Our hypothesis is targeting sEH as a novel approach for the prevention of colitis-induced carcinogenesis is through inhibiting sEH significantly to reduce the conversion of EETs to their corresponding DHETs. The proposed mechanism for the inhibition of inflammation is by suppressing inflammatory cell recruitment, modulating the arachidonic acid metabolite profile and further targeting the PPAR-gamma and NF-kB pathways to lead to an inhibition of COX-2, 5-LOX, iNOS, as well as VCAM-1. The following specific aims are performed: 1) Determine the role of sEH in colitis-induced carcinogenesis using sEH knockout mice in our novel DSS-induced carcinogenesis model, and a spontaneous colitis-carcinogenesis model in double-knockout (sEH and IL-10) mice. 2) Determine the effectiveness of the highly potent and selective sEH inhibitor as a chemopreventive agent against colitis-induced carcinogenesis in both DSS- induced and spontaneous colitis-carcinogenesis mouse models. 3) Determine the mechanism for the inhibition of colitis-induced carcinogenesis by sEH inhibitors in specimens from animals used in the aforementioned two specific aims as well as from in vitro cell lines and conditional PPAR-gamma knockout mice.
Chronic inflammation is one of the most important factors contributing to human cancer. Chronic colitis is a well-recognized risk factor of colon cancer. The goal for this project is to provide an efficient compound for prevention of colitis-induced colon cancer. Epoxyeicosatrienoic acids (EETs) are AA metabolites with anti- inflammatory activity. The inhibition of sEH prevents the complete hydrolysis of the epoxide, reducing the conversion of EETs to DHETs. Thus, EET-sEH inhibition would be efficient pathway for anti-colitis induced carcinogensis. In this project, we are in unique position to investigate the mechanism based prevention of colitis-driven carcinogenesis using potent and selective sEH inhibitor and sEH gene knockout mice combined with unique mouse models molecular pathology and pharmacology approaches.
