Prevention of bladder cancer progression by sulforaphane

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DESCRIPTION (provided by applicant): This application is focused on exploring the chemopreventive effects of bioactive components in cruciferous vegetables on bladder cancer progression. The hypothesis to be tested is that increased consumption of cruciferous vegetables, especially broccoli, may serve as an effective nutritional regimen for the prevention of bladder cancer progression and metastasis by modulating bladder tumor apoptosis and proliferation. The rationale for supporting this hypothesis is based on the followings: (1) Epidemiological investigation suggests that intake of cruciferous vegetables is associated with a lower risk of bladder cancer; (2) Our preliminary in vitro studies indicate that a bioactive component in broccoli, sulforaphane, significantly inhibited the growth of bladder cancer cell lines via modulation of apoptosis and cell cycle progression. The objectives of this pilot project are to investigate the effects of sulforaphane on prevention of bladder cancer progression and to elucidate the underlying mechanisms of action. Specific Aim 1 is to determine the effects of sulforaphane on progression of both well differentiated, low metastatic and poorly differentiated, highly metastatic human bladder tumors. Two human bladder cancer cell lines, RT4 which forms well differentiated and low metastatic tumors in vivo and 253J B-V which forms poorly differentiated and highly metastatic tumors in vivo, will be used to develop orthotopic human bladder tumor models. Sulforaphane will be evaluated for its dose-dependent effects on preventing the growth and metastasis of both RT4 and 253J B-V tumors in vivo. Specific aim 2 is to determine the effect of sulforaphane on the expression of tumor biomarkers that are related to tumor cell apoptosis and proliferation in vivo. We will determine the effects of sulforaphane on modulation of apoptotic index and the expression of apoptotic inducers (bax, p21/waft, p53, bad) and apoptosis repressors (bcl-2, bcl-x1), and tumor proliferation index and expression of cell cycle related cyclins and Cdk protein kinases. Tumor angiogenesis will also be determined by measuring microvessel density and expression of angiogenic factors (VEGF, bFGF and angiopoictin-1) and anti-angiogenic factor (angiopoietin-2). It is expected that the results will provide important information on anti-bladder cancer progression activity of sulforaphane, and provide preliminary data for R01 grant application.