Inhibition of Prostate Carcinogenesis by Apigenin

描述(由申请人提供)： 前列腺癌是最常见的，也是美国男性癌症相关死亡的主要原因之一。为了减少这种疾病的发病率，通过饮食干预进行化学预防似乎是一种令人鼓舞的方法。流行病学研究表明，大量食用水果和蔬菜可能与前列腺癌风险降低有关。这些研究与亚洲男性食用富含类黄酮的低脂肪、高纤维饮食的前列腺癌发病率世界上最低的观察结果一致。细胞培养系统的实验室研究表明，芹菜素，一种存在于水果和蔬菜中的常见黄酮类化合物，对包括皮肤、结肠癌和乳腺癌在内的许多类型的上皮性癌症具有保护作用。与这一概念一致，我们最近的研究(BBRC287：914-20,2001&Oncogene，in Press)值得注意的是，我们已经表明：i)芹菜素对正常与前列腺癌细胞的选择性反应，ii)抑制细胞生长，iii)诱导广泛的人类前列腺癌细胞的凋亡。这些发现的一个重要含义可能是芹菜素可能对人类前列腺癌的发展具有预防作用。这可能是一种通过拖延进行有效预防的方法。如果发生这种情况，那么芹菜素可以减缓人类癌细胞的生长过程，这对早期诊断为前列腺癌的患者的生存和生活质量将是重要的。然而，这些关联仍然不是决定性的，因为到目前为止还没有进行过这样的研究，可以提供芹菜素对前列腺癌发生的循证预防和干预。在目前的应用中，我们将在最近开发的模拟人类前列腺癌进行性疾病的转基因动物模型TRAMP(转基因小鼠前列腺癌)中测试这一假设。在这一应用中要检验的中心假设是，在前列腺癌发生的TRAMP模型中，芹菜素将通过调节前列腺癌细胞的凋亡机制来提供癌症预防和可能的癌症治疗效果。在实验过程中，我们将通过我们最近完善的MRI技术和99m-Tc标记的Annexin V连续监测体内肿瘤生长和细胞凋亡。这项应用的成功完成将为确定芹菜素作为一种有前景的药物在人类前列腺癌预防和治疗中的作用奠定基础。

DESCRIPTION (provided by applicant): Prostate cancer is the most common and one of the leading causes of cancer-related deaths in American males. To reduce the incidence of this disease, chemoprevention through dietary intervention appears to be an encouraging approach. Epidemiological studies suggest that high consumption of fruits and vegetables may be associated with a reduced risk of prostate cancer. These studies are consistent with the observations that Asian men who consume low fat, high-fiber diet rich in flavonoids have lowest prostate cancer incidence in the world. Laboratory studies in cell culture systems have demonstrated that apigenin, a common flavonoid present in fruits and vegetables afford protection against many types of epithelial cancers including skin, colon, and breast. Consistent with this notion, our recent studies (BBRC 287:914-20, 2001 & Oncogene, In Press) are noteworthy where we have shown i) selective response of apigenin against normal versus prostate carcinoma cells, ii) inhibition of cell growth, iii) induction of apoptosis in a wide range of human prostate carcinoma cells. An important implication of these findings could be that apigenin may have preventive effects against the development of prostate cancer in humans. This could be an effective prevention by delay. If this occurs then apigenin can slow the process of cancer cell growth in humans, it will be important for the survival and quality of life of patients diagnosed with prostate cancer at an early stage. However, these associations remain inconclusive because there is no such study conducted so far which could provide evidence-based prevention and intervention of apigenin on prostate carcinogenesis. In the present application, we will test this hypothesis in a recently developed transgenic animal model TRAMP (transgenic adenocarcinoma mouse prostate) that mimics progressive forms of human prostatic disease. The central hypothesis to be tested in this application is that apigenin will impart cancer-preventive and possibly cancer-therapeutic effect by modulating the apoptotic machinery of prostate cancer cells in TRAMP model of prostate carcinogenesis. Both in vivo tumor growth and apoptosis will be monitored serially during the experimental protocol by our recently perfected technique of MRI and 99M-Tc-labeled annexin V. A successful completion of this application will set a platform to define the role of apigenin as a promising agent against prevention and possibly therapy of prostate cancer in humans.