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p75NTR: an enhancer of fenretinide toxicity in neuroblastoma.

AbstractOBJECTIVE:
Neuroblastoma is a common, frequently fatal, neural crest tumor of childhood. Chemotherapy-resistant neuroblastoma cells typically have Schwann cell-like ("S-type") morphology and express the p75 neurotrophin receptor (p75NTR). p75NTR has been previously shown to modulate the redox state of neural crest tumor cells. We, therefore, hypothesized that p75NTR expression level would influence the effects of the redox-active chemotherapeutic drug fenretinide on neuroblastoma cells.
METHODS:
Transfection and lentiviral transduction were used to manipulate p75NTR expression in these cell lines. Sensitivity to fenretinide was determined by concentration- and time-cell survival studies. Apoptosis incidence was determined by morphological assessment and examination of cleavage of poly-ADP ribose polymerase and caspase-3. Generation and subcellular localization of reactive oxygen species were quantified using species- and site-specific stains and by examining the effects of site-selective antioxidants on cell survival after fenretinide treatment. Studies of mitochondrial electron transport employed specific inhibitors of individual proteins in the electron transport chain.
RESULTS:
Knockdown of p75NTR attenuates fenretinide-induced accumulation of mitochondrial superoxide and apoptosis. Overexpression of p75NTR has the opposite effects. Pretreatment of cells with 2-thenoyltrifluoroacetone or dehydroascorbic acid uniquely prevents mitochondrial superoxide accumulation and cell death after fenretinide treatment, indicating that mitochondrial complex II is the likely site of fenretinide-induced superoxide generation and p75NTR-induced potentiation of these phenomena.
CONCLUSION:
Modification of expression of p75NTR in a particular neuroblastoma cell line modifies its susceptibility to fenretinide. Enhancers of p75NTR expression or signaling could be potential drugs for use as adjuncts to chemotherapy of neural tumors.
AuthorsVeena Ganeshan, John Ashton, Nina F Schor
JournalCancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 71 Issue 3 Pg. 777-87 (Mar 2013) ISSN: 1432-0843 [Electronic] Germany
PMID23314735 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents
  • Antioxidants
  • Indicators and Reagents
  • NGFR protein, human
  • Nerve Tissue Proteins
  • RNA, Small Interfering
  • Reactive Oxygen Species
  • Receptors, Nerve Growth Factor
  • Fenretinide
Topics
  • Antineoplastic Agents (toxicity)
  • Antioxidants (pharmacology)
  • Apoptosis (drug effects)
  • Blotting, Western
  • Brain Neoplasms (drug therapy, genetics)
  • Cell Line, Tumor
  • Cell Membrane (drug effects)
  • Cell Survival (drug effects)
  • Electron Transport (drug effects)
  • Fenretinide (toxicity)
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Indicators and Reagents
  • Mitochondria (drug effects, metabolism)
  • Nerve Tissue Proteins (physiology, therapeutic use)
  • Neuroblastoma (drug therapy, genetics)
  • Oxidation-Reduction
  • RNA, Small Interfering (genetics)
  • Reactive Oxygen Species
  • Receptors, Nerve Growth Factor (physiology, therapeutic use)
  • Signal Transduction (drug effects)

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