Nifurtimox induces apoptosis of neuroblastoma cells in vitro and in vivo.
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.
Saulnier Sholler
Giselle L
GL
Department of Pediatrics, University of Vermont College of Medicine, Burlington, VT 05401, USA. gsholler@uvm.edu
Brard
Laurent
L
Straub
Jennifer A
JA
Dorf
Lee
L
Illeyne
Sharon
S
Koto
Karen
K
Kalkunte
Satyan
S
Bosenberg
Marcus
M
Ashikaga
Taka
T
Nishi
Rae
R
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
D000970:Antineoplastic Agents; D002395:Catecholamines; D017382:Reactive Oxygen Species; D051057:Proto-Oncogene Proteins c-akt; D053148:Caspase 3; D009547:Nifurtimox