影响自噬-溶酶体通路的vobasinyl-ibogan类型生物碱的发现及其抗肿瘤机制研究

项目名称： 影响自噬-溶酶体通路的vobasinyl-ibogan类型生物碱的发现及其抗肿瘤机制研究

项目编号： No.81473122

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 张于

作者单位： 中国科学院昆明植物研究所

项目金额： 65万元

中文摘要： 抗肿瘤药物研发多年来方兴未艾，但多数药物由于副作用大或易产生耐药性限制了其临床使用。细胞自噬因在肿瘤的发生发展过程中起到重要作用是近年来肿瘤治疗领域的新方向，但目前大多数自噬诱导剂或抑制剂因特异性和专一性差而使得该领域仍有较大的研究空间。前期我们和中国科学院遗传与发育生物学研究所合作，利用秀丽线虫为平台的筛选系统，从vobasinyl-ibogan类型吲哚生物碱中发现一类能诱导细胞自噬体的累积进而影响其与溶酶体膜融合过程的化合物。该类生物碱针对人肿瘤细胞株显著的细胞毒活性提示该类生物碱可能通过抑制肿瘤细胞自噬而起作用。前期研究还发现该类生物碱在狗牙花属植物中广泛存在。因此，有必要、也有可能从该属植物中寻找作用更强、更具专一性和特异性的该类生物碱。本项目将利用植物化学-化学合成手段定向获取该类生物碱，并研究其调控自噬-溶酶体通路的机制，有望为寻找新颖结构、作用机制的抗肿瘤先导化合物奠定基础。

中文关键词： vobasinyl-ibogan；生物碱；细胞自噬；抗肿瘤；作用机制

英文摘要： Though the research and development of anticancer drugs is in the ascendant, most of the drugs are limited in clinic by severe side effects and drug resistance. In recent years, it is generally believed that modulating the activity of autophagy could impact cancer processes, thus autophagy represents a new pharmacologic target for cancer therapy. However, there are large room for further development since the deficiencies in specificity of the inducer or inhibitor of autophagy. Through the cooperation with Institute of Genetics and Developmental Biology (CAS), a vobasinyl-ibogan type bisindole alkaloid, which could induce the accumulation of autophagosome and regulate membrane fusion was found by using C. elegans and cultured cells as models. Moreover, the alkaloid showed significant activities against various human tumor cell lines indicating it may play a role by inhibiting the autophagy in cancer cells. Previous chemical investigations suggested the vobasinyl-ibogan type alkaloids were widely distributed in the genus Ervatamia. Hence, it is necessary and possible to find more active and specific alkaloids from the genus. Our project is focused on such alkaloids by directed isolation and synthesis, and their regulatory mechanism of autophagy-lysome pathway. This study has the potential for facilitating the finding of novel anticancer drug leads.

英文关键词： vobasinyl-ibogan;alkaloid;autophagy;anticancer;mechanism