Mechanisms of Prostate Ca. Chemoprevention by Apigenin

前列腺Ca的机制。

• 批准号: 7095913
• 负责人: SANJAY GUPTA
• 金额: $ 23.53万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7095913
• 关键词: antineoplastics; athymic mouse; biological products; biological signal transduction; cancer prevention; carcinoma; cell growth regulation; chemoprevention; flavonoids; gene expression; genetically modified animals; human tissue; laboratory mouse; male; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; neoplastic cell; nonhuman therapy evaluation; nuclear factor kappa beta; pharmacokinetics; posttranslational modifications; prostate neoplasms; testosterone; tissue /cell culture; tumor necrosis factor alpha

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.

描述（由申请人提供）：通过使用针对特定分子靶标的天然药物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的观点，即大量摄入水果和蔬菜可能与降低癌症风险有关。这些研究与观察结果一致，即食用富含类黄酮的低脂肪、高纤维植物性饮食的亚洲男性前列腺癌发病率是世界上最低的。在细胞培养中进行的研究表明，芹菜素（水果和蔬菜中常见的膳食类黄酮）可以预防前列腺癌。我们实验室最近对前列腺癌临床前模型进行的研究支持了这一观察结果，即芹菜素具有癌症预防和治疗特性。芹菜素的大部分癌症预防作用归因于与炎症、增殖和细胞凋亡相关的信号转导途径的调节。 Rel/NF-kappaB 家族的成员控制重要的基因网络，调节细胞生长、增殖、炎症、细胞凋亡和针对细胞氧化还原平衡的适应性反应。 NFkappaB 的异常激活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-kappaB/p65 在人前列腺腺癌中被组成性激活，并表明该转录因子可能成为开发针对该疾病的预防和/或治疗策略的有希望的分子靶点。本提案利用了这些最近的新发现。该提案要测试的中心假设是芹菜素将通过抑制人类前列腺癌细胞中的 NF-kappaB 激活来赋予癌症预防和治疗前列腺癌的作用。我们将进一步研究体外研究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 中芹菜素抑制 NF-kappaB 激活的分子机制。具体来说，我们将通过分析关键激酶分子的水平和活性以及参与 NF-kappaB 信号通路的相关机制，研究芹菜素如何通过下调 NF-kappaB 来介导这些作用。此外，我们将采用基因过表达和抑制技术来确定芹菜素的作用是否直接由 NF-κB 的下调介导。这些结果将与从正常前列腺上皮细胞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。该提案的结果将把 NF-kappaB 定义为重要的分子靶点，将芹菜素定义为有前途的前列腺癌药物。