不同化疗药物对胶质瘤获得性SLC22A18基因耐药的逆转作用  

Effects of different chemotherapeutic drugs on reversing the acquired drug resistance to SLC22A18 gene in glioma U251 cells

作　　者：杨标 马延斌[1] 楚胜华[1] Yang Biao;Ma Yanbin;Chu Shenghua(Departmet of Neurosurgery,Shanghai Ninth People＇s Hospital Affiliated to Shanghai Jiaotong University School of Medicine,Shanghai 201999,China.)

机构地区：[1]上海交通大学医学院附属第九人民医院神经外科,上海201999

出　　处：《现代肿瘤医学》2018年第17期2670-2673,共4页Journal of Modern Oncology

基　　金：教育部留学回国人员科研启动基金项目(编号:082003);上海市卫生和计划生育委员会科研基金面上项目(编号:201540266);上海交通大学医工交叉研究基金项目(编号:YG2015MS25);上海交通大学医学院附属第三人民医院自然科学研究基金项目(编号:syz2015-015)

摘　　要：目的:探讨临床上治疗胶质瘤的不同化疗药物对胶质瘤U251细胞获得性SLC22A18耐药的逆转作用及可能的分子机制。方法:将重组腺病毒载体(Ad)介导的SLC22A18基因联合替莫唑胺(TMZ)、卡氮芥(BCNU)以及顺铂(DDP)3种常见化疗药物处理对Ad/SLC22A18产生耐药的U251-SLC22A18/R胶质瘤细胞,通过MTT比色法检测处理后胶质瘤细胞的存活率,以评估体外不同化疗药物对SLC22A18耐药的逆转作用;在体内进一步评估该逆转策略的有效性;并且通过免疫印迹等方法探讨逆转耐药的可能的分子机制。结果:在体外只有TMZ和BCNU能够使U251-SLC22A18/R细胞对Ad/SLC22A18重新敏感。进一步的研究结果表明联合TMZ和Ad/SLC22A18能在体内有效地抑制U251-SLC22A18/R细胞来源的胶质瘤生长,且联合TMZ和Ad/SLC22A18抑制作用明显比其它对照组强。Ad/SLC22A18和TMZ的联合治疗可以下调MGMT蛋白的表达,并且Ad/SLC22A18和BCNU的联合治疗可以上调Bax蛋白的表达。结论:联合应用Ad/SLC22A18和TMZ或BCNU能在体内外有效地逆转U251-SLC22A18/R细胞对SLC22A18的获得性耐药,TMZ的逆转作用可能与其诱导的MGMT蛋白低表达有关,BCNU的逆转作用可能与其诱导的Bax蛋白过度表达有关。Objective： To explore effects of different chemotherapeutic drugs on reversing the acquired drug resistance to SLC22 A18 gene and study the involved possible molecular mechanisms in U251-SLC22 A18/R glioma cells.Methods： U251-SLC22 A18/R human glioma cells that were resistant to SLC22 A18-expressing adenovector（ Ad/SLC22 A18） were treated with Ad/SLC22 A18 combined with different chemotherapeutic drugs including TMZ,BCNU and DDP. Then,the glioma cell viability was evaluated using MTT method,and apoptotic signaling proteins,including caspase-3 and caspase-8,expression of Bcl-XL and Bax,were evaluated by Western blotting analysis. Results： In vitro findings indicated that several chemotherapeutic drugs including TMZ and BCNU could reverse the acquired resistance to SLC22 A18 gene in U251-SLC22 A18/R glioma cells. Further findings illustrated that the combination of Ad/SLC22 A18 and TMZ could inhibit the growth of glioma in vivo in subcutaneous tumors established from U251-SLC22 A18/R glioma cells. The combination treatment of Ad/SLC22 A18 and TMZ could downregulate the expression of MGMT protein and the combination treatment of Ad/SLC22 A18 and BCNU could upregulate the expression of Bax protein. Conclusion： Chemotherapeutic drugs including TMZ and BCNU could overcome the acquired resistance to SLC22 A18 gene in U251-SLC22 A18/R glioma cells. The possible molecular mechanisms for TMZ to overcome the resistance might involve the downregulation of MGMT protein and the possible molecular mechanisms for BCNU to overcome the resistance might involve the upregulation of Bax protein in U251-SLC22 A18/R glioma cells.

关 键 词：胶质瘤 基因 SLC22A18 化疗 

分 类 号：R730.264[医药卫生—肿瘤]