三种植物中基于雄激素受体抑制的抗前列腺癌成分的发现及作用机制研究

项目名称： 三种植物中基于雄激素受体抑制的抗前列腺癌成分的发现及作用机制研究

项目编号： No.31500280

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 生物科学

项目作者： 王小玲

作者单位： 山东大学

项目金额： 20万元

中文摘要： 雄激素受体(AR)信号通路与前列腺癌的发生和存活密切相关，其异常活化在去势抵抗性前列腺癌(CRPC)的发展、恶化和转移中更是发挥了关键作用，因此AR是重要的抗前列腺癌药物靶点。前期发现小叶云实、见血飞和滇南木姜子提取物可显著抑制AR受体的功能，并抑制前列腺癌细胞的增殖，进一步从小叶云实中获得的高异黄酮类化合物可抑制AR受体的核转位和转录激活功能，并阻滞前列腺癌细胞周期和诱导细胞凋亡。本项目拟在前期的基础上，继续以AR抑制活性为指导，对这三种植物进行深入发掘，阐明其抗前列腺癌的物质基础。全面比较所得化合物的AR抑制活性和抗前列腺癌活性，获得强活性的目标分子并总结其构效关系。开展活性化合物抗前列腺癌和AR抑制的作用机制研究，探索其对AR信号通路关键酶、辅助调节因子和细胞因子在基因和蛋白水平的影响，阐明其AR抑制活性与阻滞肿瘤细胞周期和诱导细胞凋亡的关系，为新型抗前列腺癌药物的发现奠定基础。

中文关键词： 前列腺癌；雄激素受体；云实属；滇南木姜子；高异黄酮

英文摘要： Androgen receptor (AR) signaling is crucial for the genesis and survival of prostate cancer, the aberrant activation of which also plays a pivotal role in the development, aggression, and metastasis of castration-resistant prostate cancer (CRPC). Therefore, AR serves readily as a key target in prostate cancer treatment. In the preliminary study, we have discovered that extracts of Caesalpinia millettii, C. cucullata, and Litsea garrettii exhibited significant AR inhibiting activity, and at the same time inhibited the proliferation of several prostate cancer cell lines. Furthermore, the homoisoflavonoids isolated from C. millettii impair translocation of AR from cytoplasm to nucleus, repressed the transcriptional activity of AR, caused cell cycle arrest, and induced apoptosis on prostate cancer cells. Based on the above results, the aims of the present project are listed as follows: i) To separate the extracts of the above three plants under the guidance of AR inhibiting assay and rapidly obtain the bioactive metabolites and analogs. ii) To assay and analyze the AR inhibiting activity and anti-prostate cancer activity of the active compounds obtained, find out the most potent one, and draw the structure-activity relationship of them. iii) To test the anti-prostate cancer activity of the active compounds in vitro and in vivo, to investigate their effects on the mRNA and protein expression level of key enzymes and coactivators of the AR signaling pathway, and to clarify their michanism of action on cell functions such as proliferation, cell cycle, and apopotosis. The results of this project will make basis for the discovery of new anti-prostate cancer drugs.

英文关键词： Prostate cancer;Androgen receptor;Caesalpinia;Litsea garrettii;Homoisoflavonoids