Molecular mechanisms of fenretinide-induced apoptosis of neuroblastoma cells
Molecular mechanisms of fenretinide-induced apoptosis of neuroblastoma cells
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DOI：
10.1196/annals.1322.009
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发表时间：
2004-01-01
期刊：
影响因子：
--
通讯作者：
Redfern, CPF
中科院分区：
文献类型：
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作者：
Lovat, PE;Corazzari, M;Redfern, CPF
合成类维生素A如芬维A胺[N-（4-羟基苯基）维A酰胺]诱导神经母细胞瘤细胞凋亡，与化疗药物协同作用，并可能为神经母细胞瘤治疗的新方法提供机会。芬维A胺诱导的神经母细胞瘤细胞死亡是半胱天冬酶依赖性的，并导致细胞色素c从线粒体中释放，而不依赖于渗透性转换的变化。这是由信号通路介导的，其特征在于通过12-脂氧合酶（12-LOX）产生活性氧（ROS），以及转录因子GADD 153和BCL 2相关蛋白巴克的氧化应激依赖性诱导。芬维A胺诱导的信号传导的上游事件涉及由于鞘磷脂酶活性增加而导致的神经酰胺水平增加，以及神经酰胺随后通过葡萄糖基神经酰胺合酶和GD 3合酶代谢为神经节苷脂。这些神经节苷脂可能通过诱导GADD 153和巴克参与12-LOX的调节，导致氧化应激和凋亡。以鞘磷脂酶或下游效应物如12-LOX或GADD 153为靶点可能为开发更有效和选择性的神经母细胞瘤治疗药物提供新的方法。
Synthetic retinoids such as fenretinide [N-(4-hydroxyphenyl)retinamide] induce apoptosis of neuroblastoma cells, act synergistically with chemotherapeutic drugs, and may provide opportunities for novel approaches to neuroblastorna therapy. Fenretinide-induced cell death of neuroblastoma cells is caspase dependent and results in the release of cytochrome c from mitochondria independently of changes in permeability transition. This is mediated by a signaling pathway characterized by the generation of reactive oxygen species (ROS) via 12-lipoxygenase (12-LOX), and an oxidative-stress-dependent induction of the transcription factor, GADD153 and the BCL2-related protein BAK. Upstream events of fenretinide-induced signaling involve increased levels of ceramide as a result of increased sphingomyelinase activity, and the subsequent metabolism of ceramide to gangliosides via glucosyleeramide synthase and GD3 synthase. These gangliosides may be involved in the regulation of 12-LOX leading to oxidative stress and apoptosis via the induction of GADD153 and BAK. The targeting of sphingomyelinases or downstream effectors such as 12-LOX or GADD153 may present novel approaches for the development of more effective and selective drugs for neuroblastoma therapy.