Synthesis and reversal effect of a novel N-substituted phthalimidesugar on doxorubicin resistant of human breast cancer cells  

N-糖基取代的邻苯二甲酰亚胺新衍生物的合成与肿瘤多药耐药逆转作用研究(英文)

作　　者：易文渊[1] 李敏[1] 杨亚平[1] 吕卓远[1] 徐波[1] 韩冬[2] 李中军[1,2] 崔景荣[1] 

机构地区：[1]北京大学 天然药物及仿生药物国家重点实验室,北京100191 [2]北京大学 药学院 化学生物学系,北京100191

出　　处：《Journal of Chinese Pharmaceutical Sciences》2008年第4期319-323,共5页中国药学（英文版）

基　　金：National Natural Sciences Foundation of China (Grant No.30330690 and 30672525);Grant from the State Key Laboratory of Natural and Biomimetic Drugs,Peking University.

摘　　要：Thalidomide （α-N-phthalimido-glutarimide, TLD） is a kind of anti-angiogenic and anti-inflammatory drug, and showed effects in the treatment of several disease entities. In this study, the biological effects of a novel N-sugar substituted phthalimide （STA-35） on the regulation of multidrug resistance （MDR） to doxorubicin （ADR） were investigated. The proliferation of cancer cells was detected by a SRB assay. The activity of P-glycoprotein （P-gp） was determined by a Flow cytometry. The expression of P-gp was measured by western blotting. The results showed that STA-35 inhibited the proliferation of human breast cancer cell line MCF-7 and its ADR resistant cell line MCF-7/ADR, and the relative resistance was only 1.19. Meanwhile, STA-35 could sensitize the cytotoxicity of ADR in MCF-7/ADR cells. In addition, we found that STA-35 reduced the activity of P-gp by suppressing the P-gp expression, which was indicated by the increase in the accumulation of rhodamine 123 in MCF-7/ADR cells. These results suggested a promising application of STA-35 as the MDR reversing agent. The underlying mechanism of the effects might be attributed to the inhibition of P-gp.沙利度胺(α-N-phthalimido-glutarimide,TLD)是一种具有抗血管生成和抗炎作用的药物,对多种实体瘤有效。本文研究了N-精基取代的沙利度胺新衍生物(STA-35)对阿霉素(doxorubicin,ADR)引起的多药耐药(multidurg resistance,MDR)的调节作用。采用SRB法检测化合物对癌细胞的增殖抑制作用,应用流式细胞术测定P-糖蛋白(P-glycoprotein,P-gp)的功能,以免疫印迹方法考察P-gp的蛋白表达。实验结果表明,STA-35能够抑制人乳腺痛细胞MCF-7及其ADR耐药细胞MCF-7/ADR生长,耐药指数仅为1.19;并能增强MCF-7/ADR细胞对ADR的敏感性。此外,STA-35可以增加MCF-7/ADR细胞内罗丹明123(rhodamine 123,RH123)的聚积,减弱P-gp的功能,抑制P-gp的蛋白表达。该化合物具有多药耐药逆转作用,其分子机制可能与抑制P-gp的功能和蛋白表达相关。

关 键 词：Multidrug resistance THALIDOMIDE PHTHALIMIDE P-GLYCOPROTEIN 

分 类 号：R914[医药卫生—药物化学] R730.5[医药卫生—药学]