Cancer Chemotherapy and Pharmacology

, Volume 71, Issue 3, pp 777–787

p75NTR: an enhancer of fenretinide toxicity in neuroblastoma

Original Article

DOI: 10.1007/s00280-013-2071-7

Cite this article as:
Ganeshan, V., Ashton, J. & Schor, N.F. Cancer Chemother Pharmacol (2013) 71: 777. doi:10.1007/s00280-013-2071-7

Abstract

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.

Keywords

NeuroblastomaNeurotrophin receptorMitochondriaOxidative stressRetinoid

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  1. 1.Center for Neural Development and DiseaseUniversity of Rochester Medical CenterRochesterUSA
  2. 2.Wilmot Cancer CenterUniversity of Rochester Medical CenterRochesterUSA
  3. 3.Department of PediatricsUniversity of Rochester Medical CenterRochesterUSA