Document Detail


p75NTR: an enhancer of fenretinide toxicity in neuroblastoma.
MedLine Citation:
PMID:  23314735     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
OBJECTIVE: 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.
Authors:
Veena Ganeshan; John Ashton; Nina F Schor
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-01-13
Journal Detail:
Title:  Cancer chemotherapy and pharmacology     Volume:  71     ISSN:  1432-0843     ISO Abbreviation:  Cancer Chemother. Pharmacol.     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-02-25     Completed Date:  2013-04-08     Revised Date:  2014-03-07    
Medline Journal Info:
Nlm Unique ID:  7806519     Medline TA:  Cancer Chemother Pharmacol     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  777-87     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
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
Grant Support
ID/Acronym/Agency:
CA074289/CA/NCI NIH HHS; NS038569/NS/NINDS NIH HHS; R01 NS038569/NS/NINDS NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Antioxidants; 0/Indicators and Reagents; 0/NGFR protein, human; 0/Nerve Tissue Proteins; 0/RNA, Small Interfering; 0/Reactive Oxygen Species; 0/Receptors, Nerve Growth Factor; 187EJ7QEXL/Fenretinide
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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