Prostate Cancer Chemoprevention by Apigenin

描述（由申请人提供）：通过使用针对确定的分子靶标的天然试剂来预防癌症是一个理想的目标。流行病学研究和观察数据支持这样一种观点，即大量摄入水果和蔬菜可能与降低癌症风险有关。这些研究与以下观察结果一致：亚洲男性食用富含黄酮类化合物的低脂肪、高纤维植物性饮食，其前列腺癌发病率在世界上最低。在细胞培养中进行的研究表明，芹菜素，一种常见的膳食黄酮存在于水果和蔬菜，提供预防前列腺癌。最近在我们实验室进行的前列腺癌临床前模型的研究支持这一观察结果，即芹菜素具有癌症预防和治疗特性。芹菜素的许多癌症预防作用归因于与炎症、增殖和凋亡相关的信号转导途径的调节。Rel/NF-kappaB家族成员控制调节细胞生长、增殖、炎症、凋亡和针对细胞氧化还原平衡的适应性反应的重要基因网络。异常的NF κ B活化与许多癌症类型的发病机制有关。我们的初步研究数据表明，NF-κ B/p65在人前列腺癌中被组成性激活，并表明这种转录因子可能是一个有前途的分子靶点，用于开发针对这种疾病的预防和/或治疗策略。本提案利用了这些最近的新发现。在该提议中待测试的中心假设是芹菜素将通过抑制人前列腺癌细胞中的NF-κ B活化来赋予针对前列腺癌的癌症预防-以及治疗-效果。我们将进一步研究体外结果与体内情况的相关性。根据提出的具体目标1-4，我们将研究芹菜素在i）细胞培养系统，ii）无胸腺裸鼠异种移植物和iii）转基因小鼠TRAMP中抑制NF-κ B活化的分子机制。具体来说，我们将研究芹菜素如何通过下调NF-κ B介导这些影响，通过分析NF-κ B信号通路中涉及的关键激酶分子和相关机制的水平和活性。此外，我们将采用基因过表达和抑制技术来描述芹菜素的作用是否直接由NF-κ B的下调介导。这些结果将与从正常前列腺上皮细胞中获得的结果进行比较，本研究的结果将阐明芹菜素对前列腺上皮细胞发挥其生物活性的分子机制。这一建议的结果将确定NF-κ B作为一个重要的分子靶点和芹菜素作为有前途的药物对前列腺癌。

DESCRIPTION (provided by applicant): Cancer prevention by use of natural agents against defined molecular targets is a desirable goal. Epidemiological studies and observational data support the notion that high intake of fruits and vegetables may be associated with reduced cancer risk. These studies are consistent with the observations that Asian men who consume low fat, high-fiber plant-based diet rich in flavonoids have lowest prostate cancer incidence in the World. Studies conducted in cell culture have demonstrated that apigenin, a common dietary flavonoid present in fruits and vegetables, afford protection against prostate cancer. Recent studies conducted in our laboratory on pre-clinical model of prostate cancer supports this observation that apigenin possesses both cancer preventive- and therapeutic- properties. Much of the cancer preventive effects of apigenin are attributed due to modulations in signal transduction pathways related to inflammation, proliferation, and apoptosis. Members of the Rel/NF-kappaB family control important network of genes that regulate cell growth, proliferation, inflammation, apoptosis, and adaptive responses against cellular redox balance. Aberrant NFkappaB activation has been implicated in the pathogenesis of many cancer types. Data from our preliminary studies have shown that NF-kappaB/p65 is constitutively activated in human prostate adenocarcinoma and suggest that this transcription factor could be a promising molecular target for the development of preventive and/or therapeutic strategies against this disease. The present proposal capitalizes on these recent novel findings. The central hypothesis to be tested in this proposal is that apigenin will impart cancer preventive- as well as therapeutic- effects against prostate cancer by inhibiting NF-kappaB activation in human prostate carcinoma cells. We will further investigate the relevance of in vitro findings to in vivo situations. Under the proposed specific aims 1-4, we will investigate the molecular mechanisms that can lead to inhibition of NF-kappaB activation by apigenin in i) cell culture system, ii) athymic nude mice xenograft, and iii) transgenic mouse, TRAMP. Specifically, we will investigate how apigenin can mediate these effects through down regulation of NF-kappaB by analyzing levels and activity of key kinase molecules and associated mechanisms that are involved in the NF-kappaB signaling pathway. Moreover, we will employ gene over-expression and suppression techniques to delineate whether the effects of apigenin are directly mediated by the down regulation of NF-kappaB. These results will be compared to those obtained from normal prostate epithelial cells, and the results of this study will elucidate the molecular mechanisms by which apigenin exerts its biological activity on prostate epithelial cells. The outcome of this proposal will define NF-kappaB as an important molecular target and apigenin as promising agent against prostate cancer.