沙尔威辛抗肿瘤多药耐药分子机制及耐药特性研究(英文)  

Exploration on Anti-Multidrug-Resistant Molecular Mechanisms of Salvicine and Characterization of Salvicine-Resistant A549/SAL Cell Line

作　　者：缪泽鸿[1] 丁健[1] 

机构地区：[1]中国科学院上海生命科学研究院,上海药物研究所新药研究国家重点实验室肿瘤药理组,上海201203

出　　处：《中国科学院研究生院学报》2004年第4期549-556,共8页Journal of the Graduate School of the Chinese Academy of Sciences

基　　金：theNationalNaturalScienceFoundationofChina ( 3 0 0 70 877,3 0 3 3 0 670 ,3 0 2 2 80 3 2 ) ;KnowledgeInnovationProgramoftheChineseAcademyofSciences(KSCX2 SW 2 0 2 )andtheHigh TechResearchandDevelopment ( 863 )ProgramoftheMinistryofScienceandTechnologyofC

摘　　要：肿瘤多药耐药 (multidrugresistance ,MDR)是临床化疗成功最为严重的障碍 .首先阐明了新拓扑异构酶II抑制剂沙尔威辛对MDR肿瘤细胞直接的细胞毒性作用及下调mdr 1基因和P 糖蛋白的作用 .沙尔威辛能有效杀伤MDR细胞株 ,如K5 62 A0 2 ,KB VCR和MCF 7 ADR细胞 ,其杀伤能力与对相应亲本细胞相当 ,而明显强于几种临床常用的抗癌药物 .沙尔威辛下调mdr 1基因和P 糖蛋白的表达 ,但并不影响MRP和LRP基因 .其次 ,揭示了转录因子c jun的激活 ,在沙尔威辛下调K5 62 A0 2细胞内mdr 1基因表达及诱导凋亡过程中起着关键作用 .沙尔威辛增加K5 62 A0 2细胞的c jun表达明显早于其减少mdr 1基因的表达 ;c jun反义寡核苷酸消除沙尔威辛升高c jun蛋白、下调mdr 1基因表达的作用 .沙尔威辛还促进JNK和c jun磷酸化并增强转录因子AP1的DNA结合活性 .此外 ,c jun反义寡核苷酸还抑制沙尔威辛的凋亡诱导和细胞毒性作用 .最后 ,进一步研究发现沙尔威辛本身不引起MDR表型 .成功建立了对沙尔威辛具有 8 91倍耐药的A5 4 9 SAL细胞株 .该细胞株对抗代谢药产生 6.70倍的耐药 ,但对多种其他天然来源的抗肿瘤药物、烷化剂以及铂类化合物则缺乏交叉耐药性 .Multidrug resistance (MDR) is a major clinical problem in treating human cancers with conventional chemotherapeutic drugs. This study demonstrated that salvicine, a novel antitumor compound under clinical trial, exerted direct cytotoxicity against MDR tumor cells and down-regulated mdr-1/P-glycoprotein (P-gp) expression simultaneously. Salvicine effectively killed MDR sublines, such as K562/A02, KB/VCR and MCF-7/ADR, and parental K562, KB, and MCF-7 cell lines to an equivalent degree. Its cytotoxic activities were much more potent than those of several classical anticancer drugs. Salvicine induced the downregulation of mdr-1 gene and P-gp expression, while not affecting MRP and LRP expression. Anti-MDR mechanism exploration revealed that transcription factor c-Jun played a principal role in downregulation of mdr-1 expression and induction of apoptosis by salvicine. Levels of c-jun expression were enhanced by salvicine prior to reduction of mdr-1 expression in K562/A02 cells. Moreover, c-jun antisense oligodeoxynucleotides (AODs) prevented salvicine-stimulated enhancement of c-Jun protein and reduction of mdr-1 gene expression, but did not affect the increase in c-jun mRNA levels. Salvicine promoted phosphorylation of JNK kinase and c-Jun protein and enhanced DNA binding activity of transcription factor AP1. Additionally, c-jun AODs also inhibited salvicine-induced apoptosis and cytotoxicity. Finally, salvicine was further shown not to induce a tumor MDR phenotype. We established a salvicine-resistant tumor cell subline, A549/SAL, which displayed 8.91-fold resistance to salvicine and an average of 6.70-fold resistance to the antimetabolites. The subline, however, was not resistant to alkylating agents, platinum compounds, and other naturally-derived antineoplastics.

关 键 词：沙尔威辛 多药耐药 MDR-1基因 转录因子C-JUN A549/SAL细胞 

分 类 号：R733.7[医药卫生—肿瘤]