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Molecular mechanisms of fenretinide-induced apoptosis of neuroblastoma cells

Lookup NU author(s): Professor Penny Lovat, Bojidar Goranov, Dr Chris Redfern

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Abstract

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. © 2004 New York Academy of Sciences.


Publication metadata

Author(s): Lovat, P.E., Corazzari, M., Goranov, B., Piacentini, M., Redfern, C.P.F.

Publication type: Article

Publication status: Published

Journal: Annals of the New York Academy of Sciences

Year: 2004

Volume: 1028

Pages: 81-89

Print publication date: 01/01/2004

ISSN (print): 0077-8923

ISSN (electronic): 1749-6632

URL: http://dx.doi.org/10.1196/annals.1322.009

DOI: 10.1196/annals.1322.009

PubMed id: 15650234


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