米尔贝类抗生素逆转胶质瘤多药耐药的作用及机制研究

项目名称： 米尔贝类抗生素逆转胶质瘤多药耐药的作用及机制研究

项目编号： No.81201723

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 肿瘤学1

项目作者： 高爱丽

作者单位： 东北农业大学

项目金额： 23万元

中文摘要： 如何逆转胶质瘤化疗过程中多药耐药（MDR）现象是对其有效化疗的关键，开发新型的MDR逆转剂至关重要。前期我们研究发现米尔贝类抗生素通过抑制P-gp的表达及泵出功能有效地逆转了人乳腺癌(MCF-7/adr)的MDR。本项目在此基础上，进一步探讨其逆转胶质瘤MDR的作用及机制。首先在体外构建胶质瘤耐阿霉素细胞系C6/adr，检测米尔贝类抗生素在体外逆转胶质瘤细胞MDR的作用，并利用实时荧光定量PCR及流式细胞仪分析其逆转胶质瘤MDR的分子机制，及对主要蛋白泵功能抑制的作用机制；同时，建立体外血脑屏障（BBB）模型，检测米尔贝类抗生素增强BBB通透性而辅助其逆转MDR的作用。进一步在体内建立荷耐药胶质瘤Balb/c裸鼠模型，探讨米尔贝类抗生素在体内逆转MDR作用、主要逆转机制，以及增强BBB通透性的作用。拟阐述米尔贝类抗生素逆转胶质瘤MDR的作用及机制，对肿瘤化疗的辅助治疗提供重要理论依据。

中文关键词： 伊维菌素；莫西克汀；C6/adr；多药耐药；P-糖蛋白

英文摘要： How to reverse multidrug resistance ( MDR ) in glioma chemotherapy is key to effective chemotherapy, and development of novel MDR reversal agents is crucial. Early in our study we found that milbemycin compounds could reverse the MDR of the human breast cancer cell line (MCF-7/adr) through inhibiting the expression of P-gp and its pumping function. The project on this basis, the effects and the mechanisms of milbemycin compounds on reversing MDR of glioma are further investigated. First, adriamycin-resistant glioma cells ( C6/adr ) in vitro are established by exposing the parent C6 cell line to increasing doses of adriamycin. Then we evaluate the effects of milbemycin compounds ( nemadectin, moxidectin, milbemycin β1 and secomilbemycin D ) on reversing MDR of C6/adr cells in vitro. The molecular mechanisms of milbemycin compounds reversing multidrug resistance are researched via real-time fluorescence quantitative PCR and flow cytometric analysis, and it is tested that the milbemycin compounds inhibiting the main protein pump transport function. At the same time, the blood-brain barrier ( BBB ) model is established in vitro, and the effect of milbemycin compounds on enhancing BBB permeability is detected to develop the effects of milbemycin compounds on reversing MDR. Furthermore, we establish C6/adr xenograft i

英文关键词： ivermectin；moxidectin；C6/adr；Multidrug resistance；P-glycoprotein