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目的:利用mdr1~+的人白血病和乳腺癌多药耐药(MDR)细胞系K562/A02和MCF-7/ADR研究咯萘啶(pyronaridine,PND)对MDR的逆转作用及其机制.方法:采用MTT法、荧光分光光度法、荧光显微镜法、流式细胞仪法和RT-PCR法分别测定PND单独或与阿霉素(DOX)合用,对肿瘤细胞的生长抑制、诱导凋亡、细胞内药物浓度、mdr1基因表达的影响.结果:PND对敏感及耐药细胞均具有生长抑制作用,半数抑制剂量(IC_(50))根据不同细胞在5.10-18.66μmol/L之间;低毒剂量PND显著增强DOX对耐药细胞的细胞毒和诱导凋亡作用,且增加DOX在耐药细胞内的蓄积及减少罗丹明(Rh123)的外排.RT-PCR结果显示,PND对mdr1基因无下调作用.结论:PND可作为第三代P-糖蛋白(P-gp)抑制剂,通过下调P-gp药物外排泵功能而产生强大的逆转MDR效应.
Objective: To investigate the reversal effect of pyronaridine (PND) on MDR and its mechanism by mdr1 ~ + human leukemia and multidrug resistance (MDR) cell lines K562 / A02 and MCF-7 / ADR.Methods: MTT assay, fluorescence spectrophotometry, fluorescence microscopy, flow cytometry and RT-PCR were determined PND alone or in combination with doxorubicin (DOX) on tumor growth inhibition, apoptosis induction, intracellular Drug concentration and mdr1 gene expression.Results: PND could inhibit the growth of both sensitive and resistant cells, and the median inhibitory dose (IC 50) was between 5.10-18.66μmol / L for different cells. The low dose PND Significantly increased DOX cytotoxicity and induced apoptosis in drug-resistant cells, and increased DOX accumulation in drug-resistant cells and decreased efflux of rhodamine (Rh123) .RT-PCR results showed that PND had no effect on mdr1 gene .Conclusion: PND can act as the third generation of P-glycoprotein (P-gp) inhibitor and produce strong reversal of MDR effect by down-regulating the efflux pump function of P-gp drug.