ORIGINAL RESEARCH article
Front. Oncol.
Sec. Pediatric Oncology
Volume 15 - 2025 | doi: 10.3389/fonc.2025.1613751
OXPHOS TARGETING OF MYCN-AMPLIFIED NEUROBLASTOMA
Provisionally accepted- 1Systems Biology Ireland, School of Medicine, College of Health and Agricultural Sciences, University College Dublin, Dublin, Ireland
- 2Institute of Cancer Research (ICR), London, England, United Kingdom
- 3Conway Institute of Biomolecular and Biomedical Research, College of Engineering and Architecture, University College Dublin, Dublin, Ireland
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High risk - neuroblastoma (HR-NB) is a pediatric solid tumor with high lethality. Half of HR-NB are driven by MYCN gene amplification (MNA). These HR-NBs require high dosage chemotherapy and often relapse. Moreover, current therapies can cause severe long-term side effects and new therapies are urgently needed. This study investigates a novel therapeutic approach targeting the metabolic vulnerabilities of MNA NB cells. We discovered that Diphenyleneiodonium chloride (DPI), an inhibitor of flavoprotein enzymes and mitochondrial complex I, synergizes with mitoquinone mesylate (MitoQ), a mitochondria-targeted antioxidant in 2D and 3D in vitro models of NB. Similarly to DPI, MitoQ appears to have a greater effect on cells with higher MYCN levels. Furthermore, low nanomolar concentrations of MitoQ significantly decrease MYCN protein expression and induce differentiation of MNA cells. The DPI and MitoQ combination further synergizes with vincristine, a chemotherapeutic agent used in NB treatment. Phosphoproteomics and proteomics analysis suggests that the drug combination induces MNA NB cell death by arresting the cell cycle and inhibiting oxidative phosphorylation (OXPHOS) in the mitochondria. Thus, interference with mitochondrial metabolism may represent an effective strategy to enhance the activity of chemotherapeutic drugs in MNA-NB.
Keywords: childhood cancer, Neuroblastoma, combination therapy, Oxidative Stress, DPI, MitoQ, Metabolism
Received: 17 Apr 2025; Accepted: 29 Sep 2025.
Copyright: © 2025 Epp, Egan, Poon, Abdul Aziz, Wynne, Chesler, Halasz and Kolch. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Soraya Epp, soraya.epp@ucd.ie
Walter Kolch, walter.kolch@ucd.ie
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