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Effector mechanisms of fenretinide-induced apoptosis in neuroblastoma

Lookup NU author(s): Professor Penny Lovat, Professor Archibald Malcolm, Professor Andrew Pearson, Dr Chris Redfern

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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)-β/γ-specific antagonists, but not by an RARα-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. (C) 2000 Academic Press.


Publication metadata

Author(s): Lovat, P.E., Ranalli, M., Annichiarrico-Petruzzelli, M., Bernassola, F., Piacentini, M., Malcolm, A.J., Pearson, A.D.J., Melino, G., Redfern, C.P.F.

Publication type: Article

Publication status: Published

Journal: Experimental Cell Research

Year: 2000

Volume: 260

Issue: 1

Pages: 50-60

Print publication date: 10/10/2000

ISSN (print): 0014-4827

ISSN (electronic): 1090-2422

URL: http://dx.doi.org/10.1006/excr.2000.4988

DOI: 10.1006/excr.2000.4988

PubMed id: 11010810


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