Abstract | OBJECTIVE: 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.
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Authors | Veena Ganeshan, John Ashton, Nina F Schor |
Journal | Cancer chemotherapy and pharmacology
(Cancer Chemother Pharmacol)
Vol. 71
Issue 3
Pg. 777-87
(Mar 2013)
ISSN: 1432-0843 [Electronic] Germany |
PMID | 23314735
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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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
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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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