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Effector mechanisms of fenretinide-induced apoptosis in neuroblastoma
P E Lovat1, M Ranalli, M Annichiarrico-Petruzzelli
1Department of Endocrinology, University of Newcastle upon Tyne, Newcastle upon Tyne, NE2 4HH, United Kingdom.
Abstract:
Fenretinide is an effective inducer of apoptosis in many malignancies but its precise mechanism(s) of action in the induction of apoptosis in neuroblastoma is unclear. To characterize fenretinide-induced apoptosis, neuroblastoma cell lines were treated with fenretinide and flow cytometry was used to measure apoptosis, free radical generation, and mitochondrial permeability changes. Fenretinide induced high levels of caspase-dependent apoptosis accompanied by an increase in free radicals and the release of cytochrome c in the absence of mitochondrial permeability transition. Apoptosis was blocked by two retinoic acid receptor (RAR)-beta/gamma-specific antagonists, but not by an RARalpha-specific antagonist. Free radical induction in response to fenretinide was not blocked by the caspase inhibitor ZVAD or by RAR antagonists and was only marginally reduced in cells selected for resistance to fenretinide. Therefore, free radical generation may be only one of a number of intracellular mechanisms of apoptotic signaling in response to fenretinide. These results suggest that the effector pathway of fenretinide-induced apoptosis of neuroblastoma is caspase dependent, involving mitochondrial release of cytochrome c independently of permeability changes, and mediated by specific RARs. As the mechanism of action of fenretinide may be different from other retinoids, this compound may be a valuable adjunct to neuroblastoma therapy with retinoic acid and conventional chemotherapeutic drugs.
Insights
Fenretinide induces caspase-dependent apoptosis in neuroblastoma cells, involving cytochrome c release without mitochondrial permeability changes. Specific retinoic acid receptors mediate this process, suggesting fenretinide as a potential adjunct therapy.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Fenretinide effectively induces apoptosis in various cancers.
- The precise mechanism of fenretinide-induced apoptosis in neuroblastoma remains unclear.
Purpose of the Study:
- To elucidate the mechanism of fenretinide-induced apoptosis in neuroblastoma.
- To investigate the roles of caspases, free radicals, and mitochondrial changes.
Main Methods:
- Neuroblastoma cell lines were treated with fenretinide.
- Flow cytometry was used to measure apoptosis, free radical generation, and mitochondrial permeability.
- Specific retinoic acid receptor (RAR) antagonists were employed.
Main Results:
- Fenretinide triggered high levels of caspase-dependent apoptosis with increased free radicals and cytochrome c release, independent of mitochondrial permeability transition.
- Apoptosis was inhibited by RAR-beta/gamma antagonists but not RAR-alpha antagonists.
- Free radical generation was largely unaffected by caspase inhibitors or RAR antagonists.
Conclusions:
- Fenretinide-induced apoptosis in neuroblastoma is caspase-dependent and involves mitochondrial cytochrome c release, mediated by specific RARs.
- Free radical generation is likely one of several signaling mechanisms.
- Fenretinide may serve as a valuable adjunct therapy for neuroblastoma.