| Autor: |
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 |
| Jazyk: |
angličtina |
| Rok vydání: |
2023 |
| Předmět: |
|
| Zdroj: |
Metabolites, Vol 13, Iss 8, p 910 (2023) |
| Druh dokumentu: |
article |
| ISSN: |
2218-1989 |
| DOI: |
10.3390/metabo13080910 |
| Popis: |
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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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