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K562/ A02,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K562/A02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A549/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 withconventional chemotherapeutic drugs. This study demonstrated that salvicine, a novel antitumor compoundunder clinical trial, exerted direct cytotoxicity against MDR tumor cells and down-regulated mdr-1 PP-glycoprotein (Pgp) expression simultaneously. Salvicine effectively killed MDR sublines, such as K562/A02, KBPVCR and MCF-7PADR, and parental K562, KB, and MCF-7 cell lines to an equivalentdegree. 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 andLRP expression. Anti-MDR mechanism exploration revealed that transcription factor c-Jun played aprincipal 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 mRNAlevels. Salvicine promoted phosphorylation of JNK kinase and c-Jun protein and enhanced DNA bindingactivity of transcription factor AP1. Additionally, c-jun AODs also inhibited salvicine-induced apoptosisand cytotoxicity. Finally, salvicine was further shown not to induce a tumor MDR phenotype. Weestablished a salvicine-resistant tumor cell subline, A549/SAL, which displayed 8.91-fold resistance tosalvicine and an average of 61702fold resistance to the antimetabolites. The subline, however, was notresistant to alkylating agents, platinum compounds, and other naturally-derived antineoplastics