This is an R01 competing continuation application to study the mechanism of action of antioxidants [the isothiocyanates, sulforaphane (SFN) and phenethyl isothiocyanate (PEITC)] and the anti-inflammatory [the beta diketones, curcumin (CUR) and dibenzoylmethane (DBM)] effects, alone or in combination against colorectal cancer. In the last few years we have pursued the application of ITCs for the prevention of intestinal cancer in genetic APCmin/+ mice and the mechanisms of inhibition of intestinal cancer. We found that the ITCs induce a series of in vivo and in vitro effects including (1) in vivo inhibition of intestinal tumors in APCmin/+ by SFN and PEITC;(2) ITCs treatments resulted in decreased levels of inflammatory markers in the intestinal tumor, inhibition of cell survival and growth-related signaling pathways and modulation of cell cycle/apoptotic biomarkers;(3) ITCs induce apoptotic cell death via mitochondria cytochrome c release and activation of caspases in HT-29 colon cancer cells;(4) ITCs activate MAPKs leading to cell cycle arrest in HT-29 cells. In addition, we obtained preliminary data that using the Nrf2-/- mice, of which Nrf2 is known to be a transcriptional factor that plays critical role in cytoprotection against inflammation and oxidative stresses, Nrf2-deficient mice were found to be more susceptible to inflammatory agent DSS-induced colitis. The increased severity of colitis in Nrf2-/- mice was found to be associated with decreased expression of antioxidant/phase II detoxifying enzymes but increased in proinflammatory mediators/cytokines Furthermore, we found that PEITC protected against DSS-induced colitis in Nrf2+/+ but not in Nrf2-/- mice and that Nrf2-/- mice were more susceptible to azoxymethane (AOM)-DSS-induced colon tumors. Importantly, CUR potently protected against AOM-DSS- induced colon tumors in the Nrf2+/+ mice. Additionally, there is increasing interest and scientific rationale in the use of combinations of lower doses of chemopreventive agents possessing different mechanisms of action as a means of obtaining increased efficacy and minimized toxicity . Therefore, using our newly developed mouse colon cancer models, we would like to test our hypothesis that the antioxidants ITCs alone or in combination with anti-inflammatory CUR/DBM prevent colon cancer efficiently and safely, primarily by increasing the levels of cellular antioxidant defense enzymes and inhibition of inflammatory/pro- growth signaling molecules with three Specific Aims.
Aim 1. To investigate the anti-inflammatory effect of SFN, PEITC, CUR and DBM alone or in combination using DSS-induced experimental colitis model and chemopreventive effects of these compounds against AOM/DSS-induced colorectal carcinogenesis in Nrf2+/+ and Nrf2-/- mice.
Aim 2 is to investigate the role of Nrf2 in APC-mediated tumorigenesis using APCmin/+ and APC1638 mice and prevention by SFN, PEITC, CUR or DBM.
Aim 3 is to examine the in vivo and in vitro mechanisms of carcinogenesis and anticarcinogenesis of critical markers/genes observed in Aims 1 and 2 that are potentially conferring protection against colorectal carcinogenesis. Colorectal cancer is the third most common and leading cause of cancer mortality in the US. This is an R01 competing application to study the mechanism of dietary phytochemicals isothiocyanates (sulforaphane and PEITC) and phenolic compounds (curcumin and DBM) alone or in combination against colorectal cancer.
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