title: Nifurtimox reduces N-Myc expression and aerobic glycolysis in neuroblastoma.
abstract: Neuroblastoma is one of the most common solid tumors in childhood and usually accompanied with poor prognosis and rapid tumor progression when diagnosed with amplification of the proto-oncogene N-Myc. The amplification of N-Myc has major influence on the maintenance of aerobic glycolysis, also known as the Warburg effect. This specific switch in the conversion of pyruvate to lactate instead of the conversion of pyruvate to acetyl-coenzyme A even in the presence of oxygen has important benefits for the tumor, e.g. increased production of enzymes and enzyme substrates that are involved in tumor progression, angiogenesis and inhibition of apoptosis. The antiprotozoal drug nifurtimox, which is generally used for the treatment of infections with the parasitic protozoan Trypanosoma cruzi, has been reported to have cytotoxic properties in the therapy of neuroblastoma. However, its action of mechanism has not been described in detail yet. The presented in vitro study on the neuroblastoma cell lines LA-N-1, IMR-32, LS and SK-N-SH shows an increased production of oxidative stress, a reduced lactate dehydrogenase enzyme activity and reduced lactate production after nifurtimox treatment. Furthermore, nifurtimox leads to reduced mRNA and protein levels of the proto-oncogene protein N-Myc. Thus, the current work gives new insights into the effect of nifurtimox on tumor metabolism revealing a shifted glucose metabolism from production of lactate to oxidative phosphorylation and a reduced expression of the major molecular prognostic factor in neuroblastoma N-Myc, presenting nifurtimox as a possible adjuvant therapeutic agent against (high risk) neuroblastoma.
authors.affiliation: a University Hospital Tuebingen; Children's Hospital; Department I - General Pediatrics; Hematology/Oncology ; Tuebingen , Germany.
authors.forename: Karin Melanie
authors.initials: KM
authors.lastname: Cabanillas Stanchi
authors.affiliation: a University Hospital Tuebingen; Children's Hospital; Department I - General Pediatrics; Hematology/Oncology ; Tuebingen , Germany.
authors.forename: Gernot
authors.initials: G
authors.lastname: Bruchelt
authors.affiliation: a University Hospital Tuebingen; Children's Hospital; Department I - General Pediatrics; Hematology/Oncology ; Tuebingen , Germany.
authors.forename: Rupert
authors.initials: R
authors.lastname: Handgretinger
authors.affiliation: a University Hospital Tuebingen; Children's Hospital; Department I - General Pediatrics; Hematology/Oncology ; Tuebingen , Germany.
authors.forename: Ursula
authors.initials: U
authors.lastname: Holzer
mesh_terms: D000332:Aerobiosis; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D015870:Gene Expression; D006019:Glycolysis / Q000187:drug effects*; D006801:Humans; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism; D009547:Nifurtimox / Q000494:pharmacology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D000090063:Proto-Oncogene Mas; D017382:Reactive Oxygen Species / Q000378:metabolism; D019772:Topotecan / Q000494:pharmacology
chemical_list: D000964:Antimetabolites, Antineoplastic; C000715470:MAS1 protein, human; C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D000090063:Proto-Oncogene Mas; D017382:Reactive Oxygen Species; D019772:Topotecan; D009547:Nifurtimox
keywords: N-Myc; Warburg effect; aerobic glycolysis; neuroblastoma; nifurtimox