三种大戟科植物中抗肿瘤多药耐药活性萜类成分的发现与机制研究

肿瘤治疗中的耐药问题是肿瘤化疗或分子靶向治疗失败的主要原因，寻找和开发抗肿瘤多药耐药的新型抗癌剂或逆转剂，则是克服肿瘤耐药的重要目标。前期研究证实大戟科植物的次生代谢产物类别丰富多样，包括抗肿瘤和/或逆转多药耐药活性的萜类化合物，是研发新药和寻找先导化合物的重要来源。预实验发现大戟科巴豆亚科花戟族的部分植物乙醇提取物中有逆转多药耐药活性的组分，通过LC−MS及NMR方法识别存在萜类成分。因此，本项目拟对选定的三种大戟科植物通过活性导向−在线识别−靶向分离−结构鉴定的系统植化模式，发现活性组分中的萜类成分，结合分子对接技术虚拟筛选目标分子和靶标蛋白，以虚实结合研究模式从影响相关转运蛋白功能、细胞周期调控及凋亡诱导等方面，研究活性化合物的耐药逆转特点和机制。本研究不仅为寻找抗肿瘤先导化合物和研发创制肿瘤耐药逆转剂新型药物提供科学依据，而且对我国民族药用植物资源的综合利用和价值挖掘具有重要意义。

Drug resistance in tumor therapy is the main reason for the failure of tumor chemotherapy or targeted therapy. Thus it is important to discover and develop new anticancer agents or reversal agents that can reduce drug resistance. In previous studies, it has been confirmed that there are abundant and various secondary metabolites from Euphorbiaceae plants and these metabolites include terpenoids that can inhibit tumor growth and / or reverse the multidrug resistance. They could be an important source of new drugs and lead compounds. In preliminary study, we found active anti-multidrug resistant components from ethanol extracts of part Euphorbiaceae plants (Trib. Cluytieae Fax, Subfam. Crotonoideae), and terpenoids were identified as active components by LC-MS and NMR. We will herein take three species of Euphorbiacea plants as research objects and do a detailed study, including systematic models of phytochemistry which can help to discover terpenoids in active sites and active components through active guide—on-line identification—targeted separation—structure identification, and the molecular docking technology which can virtually screen for target molecules and target proteins. To study and identify the characteristics and mechanism of drug resistance reversal of active compounds, the research model of virtual and real combination was adopted in these aspects of the influence of transporter function, cell cycle regulation and apoptosis induction. This study not only can provide a scientific basis for the search for anti-tumor lead compounds and the development of new drugs as tumor reversal agents, but also will have great significance for the comprehensive utilization and value mining of national medicinal plant resources in China.