Synthetic, non-natural sphingolipid analogs inhibit the biosynthesis of cellular sphingolipids, elevate ceramide and induce apoptotic cell death
Synthetic, non-natural sphingolipid analogs inhibit the biosynthesis of cellular sphingolipids, elevate ceramide and induce apoptotic cell death
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DOI：
10.1016/s1388-1981(03)00122-7
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发表时间：
2003-09-22
影响因子：
4.8
通讯作者：
Gatt, S
中科院分区：
文献类型：
--
作者：
Dagan, A;Wang, CB;Gatt, S
大量研究表明鞘磷脂参与了细胞生长的信号转导和调控。几种细胞应激剂已被证明能升高神经酰胺，神经酰胺是所有鞘脂的基本前体，启动一系列事件，导致细胞周期停滞、细胞凋亡和细胞死亡。为了抑制可能导致细胞神经酰胺增加的鞘磷脂代谢途径，我们合成了神经酰胺、鞘氨醇和三甲基鞘氨醇的非天然类似物。当各自的类似物应用于HL60人髓系白血病细胞时，它们抑制鞘磷脂(SPM)和糖鞘糖脂的生物合成，并诱导细胞凋亡，从而导致细胞死亡。一种已经开发的定量细胞神经酰胺生物合成的荧光程序表明，与合成类似物孵育后神经酰胺含量增加。这些结果表明，新合成的鞘磷脂类似物有可能作为一种潜在的治疗手段应用于白血病和其他恶性肿瘤。(C)2003爱思唯尔B.V.保留所有权利。
Numerous studies have demonstrated the participation of sphingolipids in signal transduction and regulation of cell growth. Several cellular stress agents have been shown to elevate ceramide, the basic precursor of all sphingolipids, initiating a cascade of events leading to arrest of the cell cycle, apoptosis and cell death. Aiming at inhibiting metabolic pathways of sphingolipid metabolism that might lead to an increase of cellular ceramide, we have synthesized non-natural analogs of ceramide, sphingosine and trimethylsphingosine. When the respective analogs were applied to HL60 human myeloid leukemic cells they inhibited the biosynthesis of sphingomyelin (SPM) and glycosphingolipids and induced apoptosis that led to cell death. A fluorescent procedure which has been developed for quantifying the biosynthesis of cellular ceramide indicated an increase in the ceramide content following an incubation with the synthetic analogs. These results suggest that the newly synthesized sphingolipid analogs might be valuable for potential application as a therapeutic modality in leukemia and other malignancies. (C) 2003 Elsevier B.V All rights reserved.