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Nifurtimox induces apoptosis of neuroblastoma cells in vitro and in vivo.

Abstract
Neuroblastoma is the most common extracranial solid tumor in children and, when disseminated, carries a poor prognosis. Even with aggressive combinations of chemotherapy, surgery, autologous bone marrow transplant, and radiation, long-term survival remains at 30% and new therapies are needed. Recently, a patient with neuroblastoma who acquired Chagas disease was treated with nifurtimox with subsequent reduction in tumor size. The effect of nifurtimox on the neuroblastoma cell lines CHLA-90, LA1-55n, LA-N2, SMS-KCNR, and SY5Y was examined. Nifurtimox decreased cell viability in a concentration-dependent manner. Cell morphology, terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling assay, and caspase-3 activation indicate that cell death was primarily due to apoptosis. Nifurtimox also suppressed basal and TrkB-mediated Akt phosphorylation, and the cytotoxicity of nifurtimox was attenuated by a tyrosine hydroxylase inhibitor (alpha-methyl-tyrosine). Nifurtimox killed catecholaminergic, but not cholinergic, autonomic neurons in culture. In vivo xenograft models showed inhibition of tumor growth with a histologic decrease in proliferation and increase in apoptosis. These results suggest that nifurtimox induces cell death in neuroblastoma. Therefore, further studies are warranted to develop nifurtimox as a promising new treatment for neuroblastoma.
AuthorsGiselle L Saulnier Sholler, Laurent Brard, Jennifer A Straub, Lee Dorf, Sharon Illeyne, Karen Koto, Satyan Kalkunte, Marcus Bosenberg, Taka Ashikaga, Rae Nishi
JournalJournal of pediatric hematology/oncology (J Pediatr Hematol Oncol) Vol. 31 Issue 3 Pg. 187-93 (Mar 2009) ISSN: 1536-3678 [Electronic] United States
PMID19262245 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents
  • Catecholamines
  • Reactive Oxygen Species
  • Proto-Oncogene Proteins c-akt
  • Caspase 3
  • Nifurtimox
Topics
  • Animals
  • Antineoplastic Agents (pharmacology)
  • Apoptosis (drug effects)
  • Blotting, Western
  • Caspase 3 (drug effects)
  • Catecholamines (metabolism)
  • Cell Line, Tumor
  • DNA Fragmentation (drug effects)
  • Female
  • Humans
  • In Situ Nick-End Labeling
  • Mice
  • Mice, Nude
  • Neuroblastoma (drug therapy)
  • Neurons (drug effects)
  • Nifurtimox (pharmacology)
  • Phosphorylation (drug effects)
  • Proto-Oncogene Proteins c-akt (drug effects)
  • Reactive Oxygen Species
  • Xenograft Model Antitumor Assays

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