SDZ PSC 833 the drug resistance modulator activates cellular ceramide formation by a pathway independent of P-glycoprotein.
SDZ PSC 833 the drug resistance modulator activates cellular ceramide formation by a pathway independent of P-glycoprotein.
复制标题
SDZ PSC 833 是一种耐药调节剂，通过独立于 P-糖蛋白的途径激活细胞神经酰胺的形成。
DOI：
10.1016/s0304-3835(99)00353-5
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发表时间：
2000
期刊：
影响因子：
9.7
通讯作者：
Cabot,MC
中科院分区：
文献类型：
--
作者：
Goulding,CW;Giuliano,AE;Cabot,MC
SDZ PSC 833 （PSC 833）是一种新型多药耐药调节剂。最近的研究表明，PSC 833的主要作用机制是结合p -糖蛋白（P-gp），阻止化疗药物的细胞外排。我们之前报道过PSC 833增加细胞神经酰胺水平。本研究旨在确定PSC 833对神经酰胺生成的影响是否依赖于P-gp。研究人员利用对药物敏感的P-gp缺乏的人乳腺腺癌细胞系MCF-7和耐药的MCF-7/MDR1克隆10.3细胞（MCF-7/MDRl）进行了研究，这些细胞显示出稳定的MDR1 P-gp表型。MCF-7/MDR1细胞中P-gp的过度表达不会增加葡萄糖神经酰胺的水平，这一特征与多药耐药细胞有关。用PSC 833处理MCF-7和MCF-7/MDR1细胞引起类似的神经酰胺升高，且呈剂量反应性。在5.0 μM下，PSC 833将神经酰胺水平提高了4- 5倍。在两种细胞系中，神经酰胺水平的增加与存活率的下降相关。MCF-7和MCF-7/MDRl细胞对PSC 833的EC50（杀死50%细胞的药物浓度）分别为7.2±0.6和11.0±1.0 μM。c6 -神经酰胺暴露降低MCF-7细胞的存活率；而MCF-7/MDRl细胞对这种短链神经酰胺类似物具有抗性。对P-gp具有高亲和力的环孢素A对细胞进行预孵育，并没有降低暴露于PSC 833后产生的神经酰胺水平。这些结果表明PSC 833诱导的细胞神经酰胺形成独立于P-gp发生。因此，这些数据表明，经典P-gp阻滞剂逆转耐药可能受到与药物外排参数无关的因素的调节。
SDZ PSC 833 (PSC 833) is a new multidrug resistance modulator. Recent studies have shown that the principal mechanism of action of PSC 833 is to bind P-glycoprotein (P-gp) and prevent cellular efflux of chemotherapeutic drugs. We previously reported that PSC 833 increases cellular ceramide levels. The present study was conducted to determine whether the impact of PSC 833 on ceramide generation is dependent on P-gp. Work was carried out using the drug-sensitive P-gp-deficient human breast adenocarcinoma cell line, MCF-7, and drug resistant MCF-7/MDR1 clone 10.3 cells (MCF-7/MDRl), which show a stable MDR1 P-gp phenotype. Overexpression of P-gp in MCF-7/MDR1 cells did not increase the levels of glucosylceramide, a characteristic which has been associated with multidrug resistant cells. Treatment of MCF-7 and MCF-7/MDR1 cells with PSC 833 caused similar ceramide elevation, in a dose-responsive manner. At 5.0 μM, PSC 833 increased ceramide levels 4- to 5-fold. The increase in ceramide levels correlated with a decrease in survival in both cell lines. The EC50(concentration of drug that kills 50% of cells) for PSC 833 in MCF-7 and MCF-7/MDRl cells was 7.2±0.6 and 11.0±1.0 μM, respectively. C6-Ceramide exposure diminished survival of MCF-7 cells; whereas, MCF-7/MDRl cells were resistant to this short chain ceramide analog. Preincubation of cells with cyclosporine A, which has high affinity for P-gp, did not diminish the levels of ceramide generated upon exposure to PSC 833. These results demonstrate that PSC 833-induced cellular ceramide formation occurs independently of P-gp. As such, these data indicate that reversal of drug resistance by classical P-gp blockers may be modulated by factors unrelated to drug efflux parameters.