Nifurtimox reduces N-Myc expression and aerobic glycolysis in neuroblastoma

Stanchi, Karin Melanie Cabanillas; Bruchelt, Gernot; Handgretinger, Rupert; Holzer, Ursula

doi:10.1080/15384047.2015.1070987

Cited by 20 publications

(13 citation statements)

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“…Moreover, a down-regulation of all components of the aerobic mitochondrial energy metabolism without affecting mitochondrial mass was recently observed [42]. Recently, an in vitro study on the neuroblastoma cell lines LA-N-1, IMR-32, LS and SK-N-SH, showing an increased oxidative stress, a reduced lactate dehydrogenase (LDH) enzyme activity and reduced lactate production after the use of the antiprotozoal drug nifurtimox, supports the previous finding [43]. Moreover, it is becoming clearer how many oncogenic key signaling pathways converge to adapt tumor cell metabolism in order to support cancer growth and survival.…”

Section: Discussionsupporting

confidence: 63%

“…It is also true, however, that it is becoming increasingly evident that most mtDNA mutations, particularly if detected in low heteroplasmies, may result from intrinsic mtDNA replication mechanisms and are to be considered passengers events during tumorigenesis, few of which only becoming fixed in the quickly-evolving cancer cell population [52]. With respect to the few potentially pathogenic mutations found, it is worth to mention that, although aware of the low statistical power to attempt a correlation, we found no association of the former with MYCN ploidy, based on the rationale that the proto-oncogene MYCN is indirectly involved in regulating the switch off of mitochondrial function via a positive regulation of aerobic glycolysis and conversion of pyruvate to lactate [43, 53]. Its amplification, therefore, besides being associated to a poorer prognosis in neuroblastoma, may favor a relaxed selection of mtDNA variants.…”

Section: Discussionmentioning

confidence: 99%

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A comprehensive characterization of rare mitochondrial DNA variants in neuroblastoma

et al. 2016

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BackgroundNeuroblastoma, a tumor of the developing sympathetic nervous system, is a common childhood neoplasm that is often lethal. Mitochondrial DNA (mtDNA) mutations have been found in most tumors including neuroblastoma. We extracted mtDNA data from a cohort of neuroblastoma samples that had undergone Whole Exome Sequencing (WES) and also used snap-frozen samples in which mtDNA was entirely sequenced by Sanger technology. We next undertook the challenge of determining those mutations that are relevant to, or arisen during tumor development. The bioinformatics pipeline used to extract mitochondrial variants from matched tumor/blood samples was enriched by a set of filters inclusive of heteroplasmic fraction, nucleotide variability, and in silico prediction of pathogenicity.ResultsOur in silico multistep workflow applied both on WES and Sanger-sequenced neuroblastoma samples, allowed us to identify a limited burden of somatic and germline mitochondrial mutations with a potential pathogenic impact.ConclusionsThe few singleton germline and somatic mitochondrial mutations emerged, according to our in silico analysis, do not appear to impact on the development of neuroblastoma. Our findings are consistent with the hypothesis that most mitochondrial somatic mutations can be considered as ‘passengers’ and consequently have no discernible effect in this type of cancer.

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Section: Discussionsupporting

confidence: 63%

Section: Discussionmentioning

confidence: 99%

A comprehensive characterization of rare mitochondrial DNA variants in neuroblastoma

et al. 2016

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“…MYCN, an oncogene and transcription factor, amplified in neuroblastoma cells is associated with neuroblastoma growth and progression possibly by initiating both metabolic privilege mediated by WE and a high proliferative rate [11–13]. The activity of inhibitors of MYCN in high-risk neuroblastoma may partly result from inhibition of mitochondrial based metabolism [14].…”

Section: Introductionmentioning

confidence: 99%

Treatment of a chemoresistant neuroblastoma cell line with the antimalarial ozonide OZ513

et al. 2016

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BackgroundEvaluate the anti-tumor activity of ozonide antimalarials using a chemoresistant neuroblastoma cell line, BE (2)-c.MethodsThe activity of 12 ozonides, artemisinin, and two semisynthetic artemisinins were tested for activity against two neuroblastoma cell-lines (BE (2)-c and IMR-32) and the Ewing’s Sarcoma cell line A673 in an MTT viability assay. Time course data indicated that peak effect was seen 18 h after the start of treatment thus 18 h pre-treatment was used for all subsequent experiments. The most active ozonide (OZ513) was assessed in a propidium iodide cell cycle flow cytometry analysis which measured cell cycle transit and apoptosis. Metabolic effects of OZ513 in BE (2)-c cells was evaluated. Western blots for the apoptotic proteins cleaved capase-3 and cleaved PARP, the highly amplified oncogene MYCN, and the cell cycle regulator CyclinD1, were performed. These in-vitro experiments were followed by an in-vivo experiment in which NOD-scid gamma immunodeficient mice were injected subcutaneously with 1 × 106 BE (2)-c cells followed by immediate treatment with 50–100 mg/kg/day doses of OZ513 administered IP three times per week out to 23 days after injection of tumor. Incidence of tumor development, time to tumor development, and rate of tumor growth were assessed in DMSO treated controls (N = 6), and OZ513 treated mice (N = 5).ResultsIt was confirmed that five commonly used chemotherapy drugs had no cytotoxic activity in BE (2)-c cells. Six of 12 ozonides tested were active in-vitro at concentrations achievable in vivo with OZ513 being most active (IC50 = 0.5 mcg/ml). OZ513 activity was confirmed in IMR-32 and A673 cells. The Ao peak on cell-cycle analysis was increased after treatment with OZ513 in a concentration dependent fashion which when coupled with results from western blot analysis which showed an increase in cleaved capase-3 and cleaved PARP supported an increase in apoptosis. There was a concentration dependent decline in the MYCN and a cyclinD1 protein indicative of anti-proliferative activity and cell cycle disruption. OXPHOS metabolism was unaffected by OZ513 treatment while glycolysis was increased. There was a significant delay in time to tumor development in mice treated with OZ513 and a decline in the rate of tumor growth.ConclusionsThe antimalarial ozonide OZ513 has effective in-vitro and in-vivo activity against a pleiotropic drug resistant neuroblastoma cell-line. Treatment with OZ513 increased apoptotic markers and glycolysis with a decline in the MYCN oncogene and the cell cycle regulator cyclinD1. These effects suggest adaptation to cellular stress by mechanism which remain unclear.

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“…It originates from the sympathetic nervous system during embryonic development, which has a heterogeneous genetic background and substantial histological diversity, leading to differential presentation and behavior of tumor formation 3-6. Hence, the treatment for neuroblastoma might have poor outcomes, often resulting in chemo-/radio-therapy resistance 7, 8. The 5-year survival rate for patients with aggressive neuroblastoma was very low, varies from 10% to 30% 9, 10.…”

Section: Introductionmentioning

confidence: 99%

“…Nifurtimox, a primary therapeutic drug against Trypanosoma cruzi , was found effective in treating an aggressive neuroblastoma patient who happened to be infected by Trypanosoma cruzi from a blood transfusion during her treatment 11-18. A few studies in vitro presented that nifurtimox has cytotoxic features against tumor cells by inducing the formation of reactive oxygen species (ROS) under hypoxic conditions and thus triggers the apoptotic signaling pathways 8, 15, 19, 20. Yet, systematic studies to show how nifurtimox hinders the progression of neuroblastoma in vivo were not sufficient.…”

Section: Introductionmentioning

confidence: 99%

Nifurtimox Inhibits the Progression of Neuroblastoma in vivo

Kong

Zhu

et al. 2019

J. Cancer

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Neuroblastoma was one of the most life-threatening cancer developed in children, yet the conventional therapies currently used leave an unmet gap for clinical requirements. Temozolomide is the first line of drug in the treatment of neuroblastorma nowadays. Giving the fact that temozolomide treatment offered limited healing effect and patients responded divergently, an alternative beneficial path is urgently requested. Nifurtimox, a drug against Trypanosoma cruzi , was happened to find competent in treating a patient who carried aggressive neuroblastoma. Although in vitro studies demonstrated that nifurtimox has cytotoxic features against tumor cells, a systematic investigation in vivo is generally inadequate. Here we exhibited that nifurtimox could suppress the progression of neuroblastoma in vivo , while maintain the health condition to a great extent. Importantly, as comparing to temozolomide, nifurtimox presented a stronger effect on inhibiting tumor development, strongly suggesting that nifurtimox is a preferential alternative drug in treating neuroblastoma. Additionally, it was shown that Akt-GSK3β signaling cascade was involved in tumor arrest induced by nifurtimox.

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Nifurtimox reduces N-Myc expression and aerobic glycolysis in neuroblastoma

Cited by 20 publications

References 51 publications

A comprehensive characterization of rare mitochondrial DNA variants in neuroblastoma

A comprehensive characterization of rare mitochondrial DNA variants in neuroblastoma

Treatment of a chemoresistant neuroblastoma cell line with the antimalarial ozonide OZ513

Nifurtimox Inhibits the Progression of Neuroblastoma in vivo

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