Nifurtimox Induces Apoptosis of Neuroblastoma Cells In Vitro and In Vivo

Sholler, Giselle L. Saulnier; Brard, Laurent; Straub, Jennifer A; Dorf, Lee; Illeyne, Sharon; Koto, Karen; Kalkunte, Satyan; Bosenberg, Marcus; Ashikaga, Taka; Nishi, Rae

doi:10.1097/mph.0b013e3181984d91

Cited by 37 publications

(42 citation statements)

References 17 publications

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“…Nifurtimox is a nitrofuran compound that has been used since the 1970s as a primary form of therapy for Chagas' disease, a parasitic infection caused by Trypanosoma cruzi [132,133]. Preclinical studies have shown that nifurtimox inhibits neuroblastoma cell growth in vitro and in vivo [134,135], and in early-phase clinical trials tumor responses were seen in patients treated with nifurtimox at a dose of 30 mg/kg/day both as a single agent and in combination with chemotherapy [136], leading to an ongoing national phase II trial (NCT00601003).…”

Section: Treatment -Relapsed and Refractory Neuroblastomamentioning

confidence: 99%

Overview and recent advances in the treatment of neuroblastoma

Whittle

Smith

Doherty

et al. 2017

Expert Review of Anticancer Therapy

311

258

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Introduction: Children with neuroblastoma have widely divergent outcomes, ranging from cure in >90% of patients with low risk disease to <50% for those with high risk disease. Recent research has shed light on the biology of neuroblastoma, allowing for more accurate risk stratification and treatment reduction in many cases, although newer treatment strategies for children with high-risk and relapsed neuroblastoma are needed to improve outcomes. Areas covered: Neuroblastoma epidemiology, diagnosis, risk stratification, and recent advances in treatment of both newly diagnosed and relapsed neuroblastoma. Expert commentary: The identification of newer tumor targets and of novel cell-mediated immunotherapy agents may lead to novel therapeutic approaches, and clinical trials for regimens designed to target individual genetic aberrations in tumors are underway. A combination of therapeutic modalities will likely be required to improve survival and cure rates for patients with high-risk neuroblastoma.ARTICLE HISTORY

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Section: Treatment -Relapsed and Refractory Neuroblastomamentioning

confidence: 99%

Overview and recent advances in the treatment of neuroblastoma

Whittle

Smith

Doherty

et al. 2017

Expert Review of Anticancer Therapy

311

258

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“…Additionally, some T. cruzi strains are reported to be refractory to treatment (17,37). Despite these problems, nifurtimox, in cotherapy with eflornithine (NECT), has recently been added to the WHO's Essential Medicines List for treatment of West African trypanosomiasis (8,(42)(43)(44), and it is currently being subjected to clinical trials as a treatment for pediatric neuroblastoma (47,48).…”

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confidence: 99%

Trypanocidal Activity of Aziridinyl Nitrobenzamide Prodrugs

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Hall

Bashir

et al. 2010

Antimicrob Agents Chemother

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The trypanocidal agents nifurtimox and benznidazole both function as prodrugs and must undergo enzymemediated activation, a reaction catalyzed by type I nitroreductase (NTR). In the search for new parasitic therapies, we have utilized this finding to investigate whether aziridinyl nitrobenzamide derivatives have activity against bloodstream-form Trypanosoma brucei and Trypanosoma cruzi amastigotes, parasite stages that replicate in the mammalian host. For T. cruzi drug screening, we generated trypanosomes that expressed the luciferase reporter gene and optimized a mammalian infection model in a 96-well plate format. A subset of compounds having a 5-(aziridin-1-yl)-2,4-dinitrobenzyl structure was shown to be metabolized by purified T. brucei NTR and when screened against both parasite life cycle stages displayed significant growth-inhibitory properties: the most potent compounds generated 50% inhibitory concentrations of <1 M. The trypanocidal activity was shown to be NTR specific, since parasites overexpressing this enzyme were hypersensitive to the aziridinyl dinitrobenzyl agents. We conclude that members of the aziridinyl nitrobenzamide class of nitroheterocycles provide new lead structures that have the potential to treat trypanosomal infections.

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“…Igualmente y dado que el nifurtimox está siendo evaluado como medicamento en el tratamiento de algunos canceres como neuro y meduloblastoma, su actividad antitumoral ha sido demostrada en diferentes tipos de células cancerosas (30). Ensayos in vitro en líneas celulares de neuroblastoma mostraron ligeras diferencias en la toxicidad al nifurtimox siendo más susceptibles las que presentaban mayor producción de ROS (31). Se demostró además que el nifurtimox inducía apoptosis en células de neuroblastoma y en células xenotransplantadas en ratones desnudos (31).…”

Section: Discussionunclassified

Genotoxicidad del nifurtimox en deferentes líneas celulares utilizando el ensayo cometa

Escobar

2016

Rev. Médica Risaralda

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ResumenEl nifurtimox es un 5-nitrofurano sintético utilizado en el tratamiento de la enfermedad de Chagas. El objetivo de este estudio fue determinar la toxicidad celular y el daño del ADN causado por el nifurtimox en células Vero, J774, NIH/3T3 y THP-1. Se utilizó la coloración vital con azul tripan y el método colorimétrico MTT para determinar la toxicidad y el ensayo cometa alcalino para determinar el daño al ADN. Los cometas fueron contados en un microscopio de fluorescencia y el porcentaje de daño total del ADN fue calculado y clasificado de 0 (sin daño) a 4 (daño severo). En el ensayo de toxicidad, las células J774 fueron las líneas celulares más sensibles y las células THP-1 las menos sensibles al nifurtimox con valores de CC 50 34,04-138,58 µg/ml y CC 90 130,58->300 µg/ml de nifurtimox, respectivamente. En el ensayo cometa, el porcentaje de daño total de ADN a 100 µg/ml de nifurtimox fue 79,75%, 85,30% y 10,25% en células NIH/3T3, J774 y THP-1 respectivamente. En las células Vero el daño del ADN fue del 80% en células tratadas y no tratadas. El nifurtimox presentó toxicidad y genotoxicidad con actividades que dependieron del tipo de célula y de la concentración del medicamento utilizada. Es importante tomar en cuenta estas diferencias al realizar conclusiones finales de resultados obtenidos utilizando estos ensayos, especialmente el ensayo cometa.Palabras clave: nifurtimox; citotoxicidad; genotoxicidad; ensayo cometa; líneas celulares. Genotoxiciyt from Nifurtimox in comet assay AbstractNifurtimox is a synthetic 5-nitrofuran used in treating Chagas disease and potentially genotoxic in experimental models. The aim of this study was to determine the cell toxicities and DNA damage caused by nifurtimox on Vero, J774, NIH/3T3 and THP-1 cells. Vital trypan blue staining and MTT colorimetric test for cell toxicities and alkaline comet assay for DNA damage were performed. Comets were counted under fluorescent microscope and the % of DNA damage was calculated and scored from 0 (no damage) to 4 (high damage). J774 cells was the more sensitive and THP-1 cells the less one with values of CC 50 34.04-138.58µg/ml and CC 90 130.58->300 µg/ml. At a dose of 100 µg/ml of nifurtimox, DNA damage was 79.75, 85.30 % and 10.25% on NIH/3T3, J774 and THP-1 cells respectively. Vero cell showed 80% DNA damage in both treated and untreated cells. Both, cell toxicity and DNA damage were dependent on cell type and drug concentration. It is important to take these variables into account for final conclusions when these types of assays, especially comet assay are performed.Key words: nifurtimox; cytotoxicity; genotoxicity; comet assay; cell lines. IntroducciónEl nifurtimox (3-metil-4-(nitrofurfurilidenamina)-tetrahidro-4H-1,4-tiazina-1,1-dioxido, Lampit®, Bayer) es un 5-nitrofurano sintético utilizando en el tratamiento de enfermedades producidas por tripanosomas como la enfermedad de Chagas (Tripanosomiasis americana). La enfermedad de Chagas es una enfermedad sistémica compleja que afecta más de 7 millones de personas resultando en a...

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Nifurtimox Induces Apoptosis of Neuroblastoma Cells In Vitro and In Vivo

Cited by 37 publications

References 17 publications

Overview and recent advances in the treatment of neuroblastoma

Overview and recent advances in the treatment of neuroblastoma

Trypanocidal Activity of Aziridinyl Nitrobenzamide Prodrugs

Genotoxicidad del nifurtimox en deferentes líneas celulares utilizando el ensayo cometa

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