Principal Investigator/Program Director (Last, first, middle): Kong, Ah-Ng, Tony RESEARCH & RELATED Other Project Information 1. * Are Human Subjects Involved? m Yes l No 1.a. If YES to Human Subjects Is the IRB review Pending? m Yes m No IRB Approval Date: Exemption Number: 1 2 3 4 5 6 Human Subject Assurance Number 2. * Are Vertebrate Animals Used? l Yes m No 2.a. If YES to Vertebrate Animals Is the IACUC review Pending? m Yes l No IACUC Approval Date: 12-18-2006 Animal Welfare Assurance Number A3262-01 3. * Is proprietary/privileged information m Yes l No included in the application? 4.a.* Does this project have an actual or potential impact on m Yes l No the environment? 4.b. If yes, please explain: 4.c. If this project has an actual or potential impact on the environment, has an exemption been authorized or an environmental assessment (EA) or environmental impact statement (EIS) been performed? m Yes m No 4.d. If yes, please explain: 5.a.* Does this project involve activities outside the U.S. or m Yes l No partnership with International Collaborators? 5.b. If yes, identify countries: 5.c. Optional Explanation: 6. * Project Summary/Abstract 388-1-ABSTRACT-layman-rev-3-15-07HMUIi-mTeonTy.ped:f application/pdf 7. * Project Narrative 4458-7-Narrative-03-15-07-Tony.pdf Mime Type: application/pdf 8. Bibliography & References Cited 705-8-Bibliography_&_References_CitedM.pidmfe Type: application/pdf 9. Facilities & Other Resources 5912-resources-colon-2007.pdf Mime Type: application/pdf 10. Equipment 8969-Equip-colon-2007.pdf Mime Type: application/pdf Tracking Number: Other Information Page 5 OMB Number: 4040-0001 Expiration Date: 04/30/2008 Principal Investigator/Program Director (Last, first, middle): Kong, Ah-Ng, Tony 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 antioxidan |