Triple Therapy with Metformin, Ketogenic Diet, and Metronomic Cyclophosphamide Reduced Tumor Growth in MYCN-Amplified Neuroblastoma Xenografts
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...
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2023-08-01
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| author | Luca Catalano Sepideh Aminzadeh-Gohari Daniela D. Weber Rodolphe Poupardin Victoria E. Stefan William J. Smiles Julia Tevini René G. Feichtinger Sophia Derdak Martin Bilban Stefan Bareswill Markus M. Heimesaat Barbara Kofler |
| author_facet | Luca Catalano Sepideh Aminzadeh-Gohari Daniela D. Weber Rodolphe Poupardin Victoria E. Stefan William J. Smiles Julia Tevini René G. Feichtinger Sophia Derdak Martin Bilban Stefan Bareswill Markus M. Heimesaat Barbara Kofler |
| author_sort | Luca Catalano |
| collection | DOAJ |
| description | 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. |
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| publishDate | 2023-08-01 |
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| series | Metabolites |
| spelling | doaj.art-fcee0e7036e44b97ab747e0b8b617e5e2023-11-19T02:08:44ZengMDPI AGMetabolites2218-19892023-08-0113891010.3390/metabo13080910Triple Therapy with Metformin, Ketogenic Diet, and Metronomic Cyclophosphamide Reduced Tumor Growth in MYCN-Amplified Neuroblastoma XenograftsLuca Catalano0Sepideh Aminzadeh-Gohari1Daniela D. Weber2Rodolphe Poupardin3Victoria E. Stefan4William J. Smiles5Julia Tevini6René G. Feichtinger7Sophia Derdak8Martin Bilban9Stefan Bareswill10Markus M. Heimesaat11Barbara Kofler12Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical University, 5020 Salzburg, AustriaResearch Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical University, 5020 Salzburg, AustriaResearch Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical University, 5020 Salzburg, AustriaSpinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Cell Therapy Institute, Paracelsus Medical University, 5020 Salzburg, AustriaResearch Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical University, 5020 Salzburg, AustriaResearch Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical University, 5020 Salzburg, AustriaResearch Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical University, 5020 Salzburg, AustriaResearch Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical University, 5020 Salzburg, AustriaCore Facilities, Medical University of Vienna, 1090 Vienna, AustriaCore Facilities, Medical University of Vienna, 1090 Vienna, AustriaGastrointestinal 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, GermanyGastrointestinal 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, GermanyResearch Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical University, 5020 Salzburg, AustriaNeuroblastoma (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.https://www.mdpi.com/2218-1989/13/8/910neuroblastomaketogenic dietmetforminMYCNβ-oxidation |
| spellingShingle | Luca Catalano Sepideh Aminzadeh-Gohari Daniela D. Weber Rodolphe Poupardin Victoria E. Stefan William J. Smiles Julia Tevini René G. Feichtinger Sophia Derdak Martin Bilban Stefan Bareswill Markus M. Heimesaat Barbara Kofler Triple Therapy with Metformin, Ketogenic Diet, and Metronomic Cyclophosphamide Reduced Tumor Growth in MYCN-Amplified Neuroblastoma Xenografts Metabolites neuroblastoma ketogenic diet metformin MYCN β-oxidation |
| title | Triple Therapy with Metformin, Ketogenic Diet, and Metronomic Cyclophosphamide Reduced Tumor Growth in MYCN-Amplified Neuroblastoma Xenografts |
| title_full | Triple Therapy with Metformin, Ketogenic Diet, and Metronomic Cyclophosphamide Reduced Tumor Growth in MYCN-Amplified Neuroblastoma Xenografts |
| title_fullStr | Triple Therapy with Metformin, Ketogenic Diet, and Metronomic Cyclophosphamide Reduced Tumor Growth in MYCN-Amplified Neuroblastoma Xenografts |
| title_full_unstemmed | Triple Therapy with Metformin, Ketogenic Diet, and Metronomic Cyclophosphamide Reduced Tumor Growth in MYCN-Amplified Neuroblastoma Xenografts |
| title_short | Triple Therapy with Metformin, Ketogenic Diet, and Metronomic Cyclophosphamide Reduced Tumor Growth in MYCN-Amplified Neuroblastoma Xenografts |
| title_sort | triple therapy with metformin ketogenic diet and metronomic cyclophosphamide reduced tumor growth in mycn amplified neuroblastoma xenografts |
| topic | neuroblastoma ketogenic diet metformin MYCN β-oxidation |
| url | https://www.mdpi.com/2218-1989/13/8/910 |
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