樗白皮逆转P-gp介导肿瘤细胞多药耐药的物质基础研究

项目名称： 樗白皮逆转P-gp介导肿瘤细胞多药耐药的物质基础研究

项目编号： No.81202420

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 药物学、药理学

项目作者： 熊娟

作者单位： 复旦大学

项目金额： 23万元

中文摘要： 肿瘤细胞的多药耐药性（MDR）是至今癌症化疗失败的主要原因之一，其中P-糖蛋白的过度表达是导致MDR最常见的机制。因此通过抑制P-糖蛋白外排功能而逆转MDR已经成为目前肿瘤药物学研究领域的一大热点。苦木科植物臭椿（Ailanthus altissima Swingle）在我国分布广泛、资源丰富，其皮俗称樗白皮，作中药入选《中药大辞典》。本课题组前期初步研究发现樗白皮乙醇提取物及其三萜成分在耐药型癌细胞株KB-C2上表现出一定的逆转P-糖蛋白介导MDR的活性。基于此，本项目将利用高通量天然产物化学技术建立樗白皮天然化合物样品库；采用生物活性导向分离方法，对樗白皮进行系统性的化学成分（尤其是四环三萜成分）分离和结构鉴定工作，发现一批新天然化合物；对所分离得到单体化合物的生物活性在细胞水平上进行确证，对部分活性化合物进行结构修饰，以期发现基于抑制P-糖蛋白的新型MDR逆转活性先导化合物。

中文关键词： 樗白皮；三萜化合物；天然产物；抗肿瘤；多药耐药

英文摘要： Multidrug resistance (MDR) is one of the major impediments to effective cancer chemotherapy, and a primary mechanism of MDR is due to the overexpression of P-glycoprotein (P-gp). Thus, searching for MDR-reversing agents by inhibition of P-gp expression and function has been a major effort in clinical oncology. Ailanthus altissima Swingle (Family Simaroubaceae) is widely distributed in China. The bark of this plant ('chu-bai-pi' in Chinese) has been used as a tradional Chinese medicine. During our preliminary research on plant-dervied anti-tumor agents, the EtOH extract of 'chu-bai-pi' (and several triterpenoids from this extract) demonastrated potential reversing effect on P-gp-mediated MDR. Therefore, this research project is aiming to search for potent MDR-reversals from 'chu-bai-pi'. In this study, by application of high-throughput natural product chemistry methods, a natural product library from A. altissima will be generated and utilized for screening of P-gp inhibitory activity; subseqently, the chemical constituents (especially tetracyclic triterpenoids) from the barks will be thoroughly investigated under the guidance of bioassay. All the obtained natural compounds will be structurally elucidated and evaluated for their P-gp inhibitory effect, and the major bioactive compounds will be synthetically optim

英文关键词： Trunk barks of Ailanthus altissima；Triterpenoids；Natural Products；Anti-cancer activity；MDR