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Volume 13
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Article

Triple Therapy with Metformin, Ketogenic Diet, and Metronomic Cyclophosphamide Reduced Tumor Growth in MYCN-Amplified Neuroblastoma Xenografts

by
Luca Catalano
1,
Sepideh Aminzadeh-Gohari
1,
Daniela D. Weber
1,
Rodolphe Poupardin
2,
Victoria E. Stefan
1,
William J. Smiles
1,
Julia Tevini
1,
René G. Feichtinger
1,
Sophia Derdak
3,
Martin Bilban
3,4,
Stefan Bareswill
5,
Markus M. Heimesaat
5 and
Barbara Kofler
1,*
1
Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical University, 5020 Salzburg, Austria
2
Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Cell Therapy Institute, Paracelsus Medical University, 5020 Salzburg, Austria
3
Core Facilities, Medical University of Vienna, 1090 Vienna, Austria
4
Department of Laboratory Medicine, Medical University of Vienna, 1090 Vienna, Austria
5
Gastrointestinal Microbiology Research Group, Institute of Microbiology, Infectious Diseases and Immunology, Charité-University Medicine Berlin, Corporate Member of Free University Berlin, Humboldt University Berlin and Berlin Institute of Health, 12203 Berlin, Germany
*
Author to whom correspondence should be addressed.
Metabolites 2023, 13(8), 910; https://doi.org/10.3390/metabo13080910
Submission received: 7 July 2023 / Revised: 28 July 2023 / Accepted: 29 July 2023 / Published: 3 August 2023
(This article belongs to the Special Issue Metabolism and Metabolic Targeting of Neuroblastoma)
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Abstract

Neuroblastoma (NB) is a childhood cancer in which amplification of the MYCN gene is the most acknowledged marker of poor prognosis. MYCN-amplified NB cells rely on both glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) for energy production. Previously, we demonstrated that a ketogenic diet (KD) combined with metronomic cyclophosphamide (CP) delayed tumor growth in MYCN-amplified NB xenografts. The anti-diabetic drug metformin (MET) also targets complex I of the OXPHOS system. Therefore, MET-induced disruptions of mitochondrial respiration may enhance the anti-tumor effect of CP when combined with a KD. In this study, we found that MET decreased cell proliferation and mitochondrial respiration in MYCN-amplified NB cell lines, while the combination of KD, MET, and low-dose CP (triple therapy) also reduced tumor growth and improved survival in vivo in MYCN-amplified NB xenografts. Gene ontology enrichment analysis revealed that this triple therapy had the greatest effect on the transcription of genes involved in fatty acid ß-oxidation, which was supported by the increased protein expression of CPT1A, a key mitochondrial fatty acid transporter. We suspect that alterations to ß-oxidation alongside the inhibition of complex I may hamper mitochondrial energy production, thus explaining these augmented anti-tumor effects, suggesting that the combination of MET and KD is an effective adjuvant therapy to CP in MYCN-amplified NB xenografts.
Keywords: neuroblastoma; ketogenic diet; metformin; MYCN; β-oxidation neuroblastoma; ketogenic diet; metformin; MYCN; β-oxidation

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MDPI and ACS Style

Catalano, L.; Aminzadeh-Gohari, S.; Weber, D.D.; Poupardin, R.; Stefan, V.E.; Smiles, W.J.; Tevini, J.; Feichtinger, R.G.; Derdak, S.; Bilban, M.; et al. Triple Therapy with Metformin, Ketogenic Diet, and Metronomic Cyclophosphamide Reduced Tumor Growth in MYCN-Amplified Neuroblastoma Xenografts. Metabolites 2023, 13, 910. https://doi.org/10.3390/metabo13080910

AMA Style

Catalano L, Aminzadeh-Gohari S, Weber DD, Poupardin R, Stefan VE, Smiles WJ, Tevini J, Feichtinger RG, Derdak S, Bilban M, et al. Triple Therapy with Metformin, Ketogenic Diet, and Metronomic Cyclophosphamide Reduced Tumor Growth in MYCN-Amplified Neuroblastoma Xenografts. Metabolites. 2023; 13(8):910. https://doi.org/10.3390/metabo13080910

Chicago/Turabian Style

Catalano, Luca, Sepideh Aminzadeh-Gohari, Daniela D. Weber, Rodolphe Poupardin, Victoria E. Stefan, William J. Smiles, Julia Tevini, René G. Feichtinger, Sophia Derdak, Martin Bilban, and et al. 2023. "Triple Therapy with Metformin, Ketogenic Diet, and Metronomic Cyclophosphamide Reduced Tumor Growth in MYCN-Amplified Neuroblastoma Xenografts" Metabolites 13, no. 8: 910. https://doi.org/10.3390/metabo13080910

APA Style

Catalano, L., Aminzadeh-Gohari, S., Weber, D. D., Poupardin, R., Stefan, V. E., Smiles, W. J., Tevini, J., Feichtinger, R. G., Derdak, S., Bilban, M., Bareswill, S., Heimesaat, M. M., & Kofler, B. (2023). Triple Therapy with Metformin, Ketogenic Diet, and Metronomic Cyclophosphamide Reduced Tumor Growth in MYCN-Amplified Neuroblastoma Xenografts. Metabolites, 13(8), 910. https://doi.org/10.3390/metabo13080910

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