Prevention of bladder cancer progression by sulforaphane

描述（由申请人提供）： 本申请的重点是探索十字花科蔬菜中生物活性成分对膀胱癌进展的化学预防作用。有待检验的假设是，增加十字花科蔬菜，特别是西兰花的消费量，可作为一种有效的营养方案，通过调节膀胱肿瘤细胞凋亡和增殖来预防膀胱癌的进展和转移。支持这一假设的基本原理是基于以下几点：（1）流行病学调查表明，摄入十字花科蔬菜与膀胱癌的风险降低有关;（2）我们的初步体外研究表明，西兰花中的生物活性成分萝卜硫素，通过调节细胞凋亡和细胞周期进程，显着抑制膀胱癌细胞系的生长。该试点项目的目的是研究萝卜硫素对预防膀胱癌进展的影响，并阐明其潜在的作用机制。具体目的1是确定莱菔硫烷对高分化、低转移性和低分化、高转移性人膀胱肿瘤的进展的作用。两种人膀胱癌细胞系，在体内形成分化良好和低转移性肿瘤的RT 4和在体内形成分化不良和高转移性肿瘤的253 J B-V，将用于开发原位人膀胱肿瘤模型。将评价莱菔硫烷在体内预防RT 4和253 J B-V肿瘤生长和转移的剂量依赖性作用。具体目标2是确定莱菔硫烷对与体内肿瘤细胞凋亡和增殖相关的肿瘤生物标志物表达的影响。我们将确定萝卜硫素对凋亡指数和凋亡诱导因子（bax，p21/waft，p53，bad）和凋亡抑制因子（bcl-2，bcl-x1）表达的调节，以及肿瘤增殖指数和细胞周期相关的细胞周期蛋白和Cdk蛋白激酶表达的影响。还将通过测量微血管密度和血管生成因子（VEGF、bFGF和血管生成素-1）和抗血管生成因子（血管生成素-2）的表达来确定肿瘤血管生成。预计该结果将为萝卜硫素抗膀胱癌进展活性提供重要信息，并为R 01基金申请提供初步数据。

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.