Molecular mechanisms of fenretinide-induced apoptosis of neuroblastoma cells.
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 neuroblastoma 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 glucosylceramide 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.
Lovat
Penny E
PE
Northern Institute for Cancer Research, University of Newcastle upon Tyne, Newcastle upon Tyne, NE2 4HH, UK.
Corazzari
Marco
M
Goranov
Bojidar
B
Piacentini
Mauro
M
Redfern
Christopher P F
CP
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D001092:Arachidonate 12-Lipoxygenase / Q000502:physiology; D022762:CCAAT-Enhancer-Binding Proteins / Q000737:chemistry; D016923:Cell Death; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism; D017313:Fenretinide / Q000494:pharmacology*; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D018384:Oxidative Stress; D010539:Permeability; D017382:Reactive Oxygen Species; D012176:Retinoids / Q000737:chemistry; D015398:Signal Transduction; D051742:Transcription Factor CHOP; D014157:Transcription Factors / Q000737:chemistry
D000970:Antineoplastic Agents; D022762:CCAAT-Enhancer-Binding Proteins; C497249:DDIT3 protein, human; D017382:Reactive Oxygen Species; D012176:Retinoids; D014157:Transcription Factors; D051742:Transcription Factor CHOP; D017313:Fenretinide; D045304:Cytochromes c; D001092:Arachidonate 12-Lipoxygenase