【摘要】 目的 考察无毒浓度千金烷二帖化合物EM-E-11-4对P-糖蛋白（P-glycoprotein,P-gp）介导人口腔上皮癌多药耐药（multi-drug resistance,MDR）的逆转作用并检测其对P-gp功能的影响。方法 MTT比色法测定EM-E-11-4对人口腔上皮癌KB及其具有多药耐药株表型的KBV₂₀₀细胞的细胞毒活性，采用维拉帕米为参比药，非细胞毒剂量EM-E-11-4(2.5、5、10 μmol·L^-1)与3种常用抗癌药合用考察其逆转肿瘤多药耐药的作用，并计算逆转倍数。EME-11-4对P-gp的转运功能采用阿霉素蓄积实验检测。EM-E-11-4对基础与维拉帕米诱导的P-gpATPase活性采用P-gp-Glo^TM试剂盒检测。结果 EM-E-11-4能够有效逆转P-gp介导的KBV₂₀₀的多药耐药，并具有良好的剂量依赖关系。10μmol·L^-1 EM-E-11-4能够逆转KBV₂₀₀细胞对紫杉醇、长春新碱和阿霉素3种抗癌药物的耐药作用，逆转倍数分别为33.8、36.4、20.1。无细胞毒作用的EM-E-11-4对P-gp的转运功能有显著抑制作用，并且能够增加阿霉素在肿瘤细胞内的蓄积，具有良好的浓度依赖性。同时，EM-E-11-4能明显抑制维拉帕米刺激的重组P-gp的ATPase活性。结论 EM-E-11-4能逆转P-gp介导的肿瘤多药耐药，其作用机制与抑制P-gp的转运功能有关，为其临床治疗口腔上皮癌肿瘤多药耐药提供了理论依据。更多还原

【Abstract】 Objective To investigate the ability of a natural product EM-E-11-4 at non-cytotoxic concentrations to reverse P-gp-mediated multidrug resistance（MDR） in human oral epithelial cancer cells KBV₂₀₀ and to reveal the mechanism of action. Methods The effect of EM-E-11-4 on the growth of KB cells and the corresponding resistant cells KBv₂₀₀ was determined by MTT assay. Using VRP as positive control, the ability of non-cytotoxic concentrations of EM-E-11-4(2.5,5, 10 μmol·L^-1) with/without such chemotherapeutic agents as paclitaxel vincristine and adriamycin to reverse MDR was evaluated, while the reversal folds（RF） of EM-E-11-4 and VRP were calculated and compared. The effect of EME-11-4 and VRP on the accumulation and efflux function of P-gp was studied. Furthermore, the effect of EM-E-11-4 on the ATPase activity of P-gp was measured by Pgp-Glo^TM kit. Results 10 μmol·L^-1 of EM-E-11-4 effectively reversed the MDR-phenotype of KBv₂₀₀ cells to paclitaxel, vincristine and adriamycin. The RF was 33.8、36.4 and 20.1, respectively.In addition, the P-gp functional study suggested that EM-E-11-4 elevated the intracellular accumulation of adriamycin in a dose-dependent manner. EM-E-11-4 suppressed VRP-stimulated ATPase activity of P-gp in a dose-dependent manner.Conclusion EM-E-11-4 can be a potential agent that can overcome P-gp-mediated MDR by suppressing the transport function of P-gp.更多还原