鬼臼类化合物损伤微管蛋白结构诱导肿瘤细胞凋亡过程的信号转导机制

项目名称： 鬼臼类化合物损伤微管蛋白结构诱导肿瘤细胞凋亡过程的信号转导机制

项目编号： No.81503112

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 赵巍

作者单位： 湖北工业大学

项目金额： 18.5万元

中文摘要： 微管蛋白抑制剂通过引起微管正常组装紊乱诱导肿瘤细胞凋亡发挥抗肿瘤活性，然而微管蛋白结构损伤诱导肿瘤细胞凋亡过程的信号转导机制尚不明晰。前期，课题组以微管蛋白为靶标合成了一系列硫取代鬼臼类化合物，其作用于人肺癌A549细胞后，与公认的微管蛋白抑制剂秋水仙碱相比，引起胞内微管收缩更为明显，对细胞周期G2/M期阻滞率和诱导凋亡率均显著高于秋水仙碱。本项目拟以上述硫取代鬼臼类化合物作为微管蛋白抑制剂的典型代表，探索鬼臼类化合物损伤微管蛋白结构诱导肿瘤细胞凋亡过程的信号转导机制。首先，研究鬼臼类化合物损伤微管蛋白结构引起微管组装紊乱过程，解析微管组装紊乱所激发的信号通路；然后，检测细胞凋亡途径中标志性凋亡蛋白，确定细胞凋亡途径；最后，研究上述信号通路与细胞凋亡途径的内在联系，从而阐明鬼臼类化合物损伤微管蛋白结构诱导肿瘤细胞凋亡过程的信号转导机制，预期将为微管蛋白抑制剂抗肿瘤分子机制研究提供理论支撑。

中文关键词： 硫取代鬼臼类化合物；微管蛋白抑制剂；信号转导；细胞凋亡；分子机制

英文摘要： As an important class of specific anticancer drugs, tubulin inhibitors could induce tumor cell apoptosis by damaging tubulin structure. However, its mechanism is still unknown. Our group synthesized a series of the sulfur-substituted podophyllum compounds, which more seriously inhibited the microtubule assembly in the human lung carcinoma A549 cells compared with colchicines. Not only the G2/M phase arrest ratio but also the apoptosis ratio of the sulfur-substituted podophyllum compound was higher than that of colchicines. By taking the sulfur-substituted podophyllum compound as typical tubulin inhibitor, the project is to study the signal transduction mechanism of podophyllum compounds inducing tumor cell apoptosis by damaging tubulin structure. Firstly, the process of podophyllum compounds damaging the structure of tubulin and its injury on the microtubule assembly will be studied to clarity which signals transduction pathways will be mediated by microtubule assembly disorder. Secondly, the expression of apoptosis signaling protein will be analyzed to confirm the apoptosis pathway. Thirdly, the above relationship between the signal transduction pathways and the apoptosis pathways will be studied to elucidate the signal transduction mechanism of podophyllum compounds inducing tumor cell apoptosis by damaging tubulin structure. This work will provid a theory fundamental for the antitumor mechanism of the tubulin inhibitors.

英文关键词： Sulfur-substituted podophyllum compounds;Tubulin inhibitor;Signal transduction;Cell apoptosis;Molecular mechanism