title: 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.
authors.affiliation: Department of Pediatrics, University of Vermont College of Medicine, Burlington, VT 05401, USA. gsholler@uvm.edu
authors.forename: Giselle L
authors.initials: GL
authors.lastname: Saulnier Sholler
authors.forename: Laurent
authors.initials: L
authors.lastname: Brard
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Straub
authors.forename: Lee
authors.initials: L
authors.lastname: Dorf
authors.forename: Sharon
authors.initials: S
authors.lastname: Illeyne
authors.forename: Karen
authors.initials: K
authors.lastname: Koto
authors.forename: Satyan
authors.initials: S
authors.lastname: Kalkunte
authors.forename: Marcus
authors.initials: M
authors.lastname: Bosenberg
authors.forename: Taka
authors.initials: T
authors.lastname: Ashikaga
authors.forename: Rae
authors.initials: R
authors.lastname: Nishi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D053148:Caspase 3 / Q000187:drug effects; D002395:Catecholamines / Q000378:metabolism; D045744:Cell Line, Tumor; D053938:DNA Fragmentation / Q000187:drug effects; D005260:Female; D006801:Humans; D020287:In Situ Nick-End Labeling; D051379:Mice; D008819:Mice, Nude; D009447:Neuroblastoma / Q000188:drug therapy*; D009474:Neurons / Q000187:drug effects; D009547:Nifurtimox / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects; D017382:Reactive Oxygen Species; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D002395:Catecholamines; D017382:Reactive Oxygen Species; D051057:Proto-Oncogene Proteins c-akt; D053148:Caspase 3; D009547:Nifurtimox