中文摘要：

研究新型紫杉烷类化合物NPB304逆转肿瘤多药耐药的作用。MTT法测定化疗药物的IC50，Westernblotting方法分析P．糖蛋白fP—gP）的表达，分别通过罗丹明123（Rh123）蓄积实验和分析试剂盒测定化合物对P—gP功能及P—gPATPase活性的影响，采用分子对接预测化合物与P—gp结合能力的强弱，用MDCKII和MDR1-MDCKII细胞模型分析NPB304的跨膜转运。在KBV细胞中，NPB304具有多药耐药逆转作用；在MCF-7／paclitaxel细胞中，NPB304协同P-gp抑制剂维拉帕米增强逆转耐药的活性，10μmol·L^-1维拉帕米与paclitaxel合用时逆转倍数为56．5倍，合用NPB304增加耐药逆转倍数：NPB304与维拉帕米合用时协同增加Rh123在耐药细胞中的蓄积，NPB304（0～1μmol·L^-1）增强维拉帕米激活P-gPATPase活性的作用；NPB304与P-gP的TM区存在疏水相互作用，与TM区A链的结合力较强；NPB304在较低浓度（0～1．5μmol·L^-1）时激活P-gPATPase，发挥抑制P—gP功能的作用，但不具有明显的P-gp底物特征。NPB304通过抑制P-gP的功能活性发挥自身及协同维拉帕米逆转耐药的作用。

英文摘要：

The tumor multidrug resistance reversal effect of NPB304, a novel taxane, was studied. MTT assay was used to determine the ICs0 of chemotherapy drugs. Western blotting assay was applied to analyze the expression of P-glycoprotein （P-gp）. The effect of compounds on the P-gp function and P-gp ATPase activity was determined by rhodamine 123 （Rh123） accumulation assay and analysis kit, respectively. Molecular docking was employed to predict the binding force between compounds and P-gp. Transmembrane transport of NPB304 was analyzed using MDCK II and MDR1-MDCKII cell model. NPB304 displayed multidrug resistance reversal effect on KBV cells and MCF-7/paclitaxel cells, NPB304 collaborative with P-glycoprotein （P-gp） inhibitors verapamil enhanced the reversal activity, specifically, 10 μmol·L^-1 verapamil in combination with paclitaxel reversed resistance by 56.5-fold, while combined with NPB304 increased the reversal fold; NPB304 synergistically increased Rh123 accumulation in the resistant cells when combined with verapamil, and NPB304 at 0-1 μmol·L^-1 enhanced the ATPase activity activated by verapamil was observed. NPB304 existed the hydrophobic interactions with the TM regions of P-gp, and the binding force between NPB304 and the A chain of the TM region was stronger. P-gp ATPase activity assay demonstrated NPB304 at lower concentrations（0-1.5 μmol·L^-1） could activate the P-gp ATPase, playing a role on inhibition of P-gp function. However, NPB304 did not have an obvious feature of P-gp substrate. NPB304 exerted itself and synergy with verapamil activity on reversing tumor resistance via inhibiting the P-gp function,