Many epidemiological studies have supported that frequent consumption of cruciferous vegetables such as broccoli, cauliflower, cabbage, watercress and Brussels sprout is associated with a decreased risk in various type of human cancer including colon, lung, esophageal and stomach. Cruciferous vegetables contain high quantity of isothiocyanates (ITCs) including sulforaphane (SUL) and phenethylisothiocyanate (PEITC). These compounds have been shown to inhibit chemically induced carcinogenesis in various animal models. Our long-term goal is to elucidate the mechanisms of inhibition of carcinogenesis by ITCs. In this renewal application, we will test the hypothesis that ITC prevents carcinogenesis by inhibiting cellular proliferation and enhancing apoptosis in the intestine by examining the dose-response of the ITCs and the related pharmacokinetics, metabolism and tissue levels of the drugs, to examine the in vivo mechanism and to elucidate the related molecular mechanisms using in vitro cell culture models. The following specific aims are designed to address our hypothesis. 1. Investigate the dose-response of inhibition of carcinogenesis by ITCs in Min intestinal neoplasia mice. We will study the inhibition of cell proliferation and tumor progression by different doses of ITCs, SUL and PEITC, in short-term as well as long-term treatments. We will also examine the tumor and plasma levels of ITCs and their metabolites under different experimental conditions using LC/MS and characterize the relationship between drug levels and response. The tumor and plasma levels of these compounds will serve as potential references for evaluating the mechanisms of anti-carcinogenesis and for comparing results in animals and humans in the future. 2. Examine the in vivo mechanisms of inhibition of carcinogenesis by ITCs in Min intestinal neoplasia mice. We will study whether the inhibition of cell proliferation and tumor progression by ITCs, SUL and PEITC described in Aim 1 above, could be related to the activity of pertinent signal transduction pathways (such as MAPKcaspases- apoptosis and APC-beta-catenin-cell cycle pathways) in long-term and short-term animal experiments. DNA microarray analysis of tumor samples after ITC treatments will be conducted to complement and to further delineate the mechanisms of ITCs. 3. Elucidate in-depth mechanistic studies in colon cancer cell lines on the signal transduction pathways leading to growth inhibition and apoptosis induced by ITCs, including the role of APC-beta-catenin-cell cycle arrest pathway and MAPK-caspase-apoptosis pathway. Additional signaling pathways will be explored based on the DNA microarray analysis described above in Aim 2. These studies will complement the studies in Aim 2 and will provide the basic understanding of the chemopreventive actions of isothiocyanates in general.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA073674-09
Application #
7230449
Study Section
Special Emphasis Panel (ZRG1-CAMP (04))
Program Officer
Crowell, James A
Project Start
1999-04-22
Project End
2007-11-30
Budget Start
2007-05-01
Budget End
2007-11-30
Support Year
9
Fiscal Year
2007
Total Cost
$270,760
Indirect Cost
Name
Rutgers University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
001912864
City
New Brunswick
State
NJ
Country
United States
Zip Code
08901
Ramirez, Christina N; Li, Wenji; Zhang, Chengyue et al. (2017) In Vitro-In Vivo Dose Response of Ursolic Acid, Sulforaphane, PEITC, and Curcumin in Cancer Prevention. AAPS J 20:19
Cheung, Ka Lung; Lee, Jong Hun; Khor, Tin Oo et al. (2014) Nrf2 knockout enhances intestinal tumorigenesis in Apc(min/+) mice due to attenuation of anti-oxidative stress pathway while potentiates inflammation. Mol Carcinog 53:77-84
Su, Zheng-Yuan; Shu, Limin; Khor, Tin Oo et al. (2013) A perspective on dietary phytochemicals and cancer chemoprevention: oxidative stress, nrf2, and epigenomics. Top Curr Chem 329:133-62
Lee, Jong Hun; Khor, Tin Oo; Shu, Limin et al. (2013) Dietary phytochemicals and cancer prevention: Nrf2 signaling, epigenetics, and cell death mechanisms in blocking cancer initiation and progression. Pharmacol Ther 137:153-71
Wang, Hu; Khor, Tin Oo; Yang, Qian et al. (2012) Pharmacokinetics and pharmacodynamics of phase II drug metabolizing/antioxidant enzymes gene response by anticancer agent sulforaphane in rat lymphocytes. Mol Pharm 9:2819-27
Wang, Hu; Lin, Wen; Shen, Guoxiang et al. (2011) Development and validation of an LC-MS-MS method for the simultaneous determination of sulforaphane and its metabolites in rat plasma and its application in pharmacokinetic studies. J Chromatogr Sci 49:801-6
Kim, Jung-Hwan; Chen, Chi; Tony Kong, Ah-Ng (2011) Resveratrol inhibits genistein-induced multi-drug resistance protein 2 (MRP2) expression in HepG2 cells. Arch Biochem Biophys 512:160-6
Saw, Constance Lay Lay; Kong, Ah-Ng Tony (2011) Nuclear factor-erythroid 2-related factor 2 as a chemopreventive target in colorectal cancer. Expert Opin Ther Targets 15:281-95
Cheung, Ka Lung; Yu, Siwang; Pan, Zui et al. (2011) tBHQ-induced HO-1 expression is mediated by calcium through regulation of Nrf2 binding to enhancer and polymerase II to promoter region of HO-1. Chem Res Toxicol 24:670-6
Swanson, Hollie I; Njar, Vincent C O; Yu, Zhen et al. (2010) Targeting drug-metabolizing enzymes for effective chemoprevention and chemotherapy. Drug Metab Dispos 38:539-44

Showing the most recent 10 out of 53 publications