Ceramide synthesis and metabolism as a target for cancer therapy
Ceramide synthesis and metabolism as a target for cancer therapy
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DOI：
10.1016/j.canlet.2003.08.034
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发表时间：
2004-04-08
期刊：
影响因子：
9.7
通讯作者：
Kolesnick, RN
中科院分区：
文献类型：
--
作者：
Reynolds, CP;Maurer, BJ;Kolesnick, RN
鞘磷脂，包括神经酰胺和鞘氨醇，是细胞膜的基本结构成分，也具有调节细胞增殖、生存和死亡的信使功能。神经酰胺的外源性应用是细胞毒性的，细胞暴露在放射或化疗下与神经酰胺水平的增加有关，这是由于神经酰胺的从头合成增强、鞘磷脂分解代谢或两者兼而有之。神经酰胺可以通过糖基化、酰化或分解代谢为鞘氨醇，然后被磷酸化为抗细胞凋亡的鞘氨醇I-磷酸，从而代谢成毒性较低的形式。葡萄糖神经酰胺合成酶的过度表达可增强对阿霉素的耐药性，提示抑制神经酰胺代谢或分解代谢可能增强肿瘤化疗效果。几种抗癌药物，包括细胞毒性维甲酸，芬维甲素(4-HPR)，已被证明至少部分地通过从头合成增加肿瘤细胞神经酰胺的作用。4-HPR和神经酰胺作用和/或代谢调节剂的组合在临床前模型中显示出增强的抗肿瘤活性，对非恶性细胞的毒性最小，并且对耐标准细胞毒剂的肿瘤细胞系具有非p53依赖的有效作用。神经酰胺代谢抑制剂与4-HPR和其他细胞毒剂联合使用的第一阶段试验正在开发中。因此，通过调控鞘脂代谢来增强肿瘤细胞神经酰胺的药理作用正在实现，并为肿瘤化疗提供了一种新的途径。(C)2003爱思唯尔爱尔兰有限公司。保留所有权利。
Sphingolipids, which include ceramides and sphingosine, are essential structural components of cell membranes that also have messenger functions that regulate the proliferation, survival, and death of cells. Exogenous application of ceramide is cytotoxic, and exposure of cells to radiation or chemotherapy is associated with increased ceramide levels due to enhanced de novo synthesis, catabolism of sphingomyelin, or both. Ceramide can be metabolized to less toxic forms by glycosylation, acylation, or by catabolism to sphingosine, which is then phosphorylated to the anti-apoptotic sphingosine I-phosphate. Glucosylceramide synthase overexpression has been shown to enhance resistance to doxorubicin, suggesting that inhibition of ceramide metabolism or catabolism might enhance cancer chemotherapy. Several anticancer agents, including the cytotoxic retinoid, fenretinide (4-HPR), have been shown to act, at least in part, by increasing tumor cell ceramide via de novo synthesis. Combinations of 4-HPR and modulators of ceramide action and/or metabolism demonstrated increased anti-tumor activity in pre-clinical models with minimal toxicity for non-malignant cells, and were effective in a p53-independent manner against tumor cell lines resistant to standard cytotoxic agents. Phase I trials of ceramide metabolism inhibitors in combination with 4-HPR and with other cytotoxic agents are in development. Thus, pharmacological manipulation of sphingolipid metabolism to enhance tumor cell ceramide is being realized and offers a novel approach to cancer chemotherapy. (C) 2003 Elsevier Ireland Ltd. All rights reserved.