This Project focuses on determining the cancer-preventive activity of isothiocyanates (ITCs) in the bladder. The hypothesis to be tested is that selected ITCs can suppress bladder carcinogenesis by disrupting multiple steps in the carcinogenic process: induction of Phase 2 enzymes, induction of apoptosis, and inhibition of cell proliferation. Molecular markers relevant to these biological events, as well as inhibition of tumorigenesis, will be studied. Bladder cancer is an important health problem; effective chemopreventive agents are needed. ITCs are abundant in vegetables and many are known anticarcinogens in non-bladder animal organs. Ingested ITCs are efficiently absorbed and almost exclusively excreted in urine as N-acetylcysteine conjugates (NAC-ITCs), which also are anticarcinogens and can release ITCs, making the bladder epithelium the most exposed tissue to ITCs/NAC-ITCs. The overwhelming majority of bladder cancers originate from the epithelial cells. Four dietary ITCs that displayed potent anti-carcinogenic activity in non-bladder animal organs and their NAC conjugates will be evaluated.
Aim 1 is designed to see whether ITCs or NAC-ITCs effectively induce critical Phase 2 detoxification enzymes, including glutathione transferase, quinone reductase-1, and UDPglucuronosyltransferase, whose deficiencies have been linked to increased bladder carcinogenesis.
Aim 2 will determine the protective efficacy of ITCs or NAC-ITCs against carcinogen-induced DNA damage in bladder epithelial cells, using total DNA adducts and unscheduled DNA synthesis (UDS) as markers. Imbalance between apoptosis and proliferation also is a risk factor of bladder cancer.
Aim 3 will determine whether ITCs or NAC-ITCs can correct the imbalance between apoptosis and proliferation associated with bladder carcinogenesis: Do ITCs or NAC-ITCs induce apoptosis and/or inhibit cell cycle progression in bladder cancer cells? If so, what is the underlying mechanism(s)? Aim 4 will evaluate in rivo the effect of orally administered ITCs on important biomarkers, including the Phase 2 enzymes described in Aim 1, apoptosis (TUNEL), and proliferation (PCNA) in the bladder epithelium of F344 rats.
Aim 5 will determine the efficacy of an orally administered ITC in inhibiting N-butyl-N- (4-hydroxybutyl)-nitrosamine-induced bladder tumorigenesis in F344 rats.
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