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Molecular Mechanisms of Fenretinide‐Induced Apoptosis of Neuroblastoma Cells
Author(s) -
LOVAT PENNY E.,
CORAZZARI MARCO,
GORANOV BOJIDAR,
PIACENTINI MAURO,
REDFERN CHRISTOPHER P. F.
Publication year - 2004
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1196/annals.1322.009
Subject(s) - fenretinide , ceramide , apoptosis , neuroblastoma , microbiology and biotechnology , oxidative stress , lipid signaling , programmed cell death , reactive oxygen species , chemistry , sphingomyelin , cancer research , retinoid , biology , biochemistry , cell culture , receptor , retinoic acid , genetics , membrane , gene
A bstract : 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.