Cabot M C, Han T Y, Giuliano A E
John Wayne Cancer Institute at Saint John's Health Center, Santa Monica, CA 90404, USA.
FEBS Lett. 1998 Jul 17;431(2):185-8. doi: 10.1016/s0014-5793(98)00744-3.
In this study we demonstrate that the multidrug resistance (MDR) modulator PSC 833 is a potent agonist of ceramide metabolism. When added with [3H]serine or [3H]palmitic acid to the culture medium of MCF-7 cells, PSC 833, in a dose-responsive fashion (1-10 microM), increased the levels of [3H]ceramide as much as 16-fold over control. The actual increase in ceramide mass was verified by thin-layer chromatographic chars. Cellular sphingomyelin radioactivity did not decrease during treatment, indicating that PSC 833 does not elicit ceramide formation through a sphingomyelinase pathway. Inclusion of fumonisin B1, an inhibitor of ceramide synthase, blocked formation of ceramide by PSC 833. The results of cell proliferation assays demonstrated a clear correlation between PSC 833 elicitation of ceramide formation and increased cytotoxicity. The MDR modulator and chemical cousin of PSC 833, cyclosporin A, had little impact on cellular ceramide formation. At a concentration of 2.5 microM, cyclosporin A and PSC 833 treatment increased ceramide formation by 20% and 7.5-fold, respectively. These results reveal a new action of PSC 833 which may contribute to its potency as a drug resistance modulator.
在本研究中，我们证明多药耐药（MDR）调节剂PSC 833是神经酰胺代谢的强效激动剂。当将其与[3H]丝氨酸或[3H]棕榈酸添加到MCF-7细胞的培养基中时，PSC 833以剂量响应方式（1-10 microM）使[3H]神经酰胺水平比对照增加多达16倍。神经酰胺质量的实际增加通过薄层色谱法得以验证。在处理过程中细胞鞘磷脂放射性并未降低，这表明PSC 833并非通过鞘磷脂酶途径引发神经酰胺的形成。加入神经酰胺合酶抑制剂伏马菌素B1可阻断PSC 833诱导的神经酰胺形成。细胞增殖试验结果表明，PSC 833诱导神经酰胺形成与细胞毒性增加之间存在明显相关性。PSC 833的MDR调节剂及化学类似物环孢素A对细胞神经酰胺形成影响很小。在2.5 microM浓度下，环孢素A和PSC 833处理分别使神经酰胺形成增加20%和7.5倍。这些结果揭示了PSC 833的一种新作用，这可能有助于其作为耐药调节剂的效力。
