Metformin enhanced the effect of a Ketogenic diet in MYCN amplified Neuroblastoma xenografts

Neuroblastoma (NB) is a childhood cancer in which the MYCN amplification is the most acknowledged marker of poor prognosis. MYCN-amplified NB cells showed to rely on both glycolysis and oxidative phosphorylation system (OXPHOS) for energy production . Previously, we revealed that a ketogenic diet (KD) slowed the tumor growth in MYCN NB xenografts, when combined with classical cytotoxic therapy cyclophosphamide (CP). Metformin (MET) is a compound that targets complex I of the OXPHOS system. Therefore, the aim of this study was to elucidate whether MET can enhance the anti-tumorigenic effects of a KD in NB. Our result indicated that MET decreasedcell proliferation andrespiration in NB cells in vitro. The combination of KD, MET and low dose of chemotherapyreduced also the tumor growth and improved survival in NB xenografts. GO enrichment analysis revealed fatty acid ß-oxidation as the most upregulated process resulting from the addition of MET to KD. The differential expression of CPT1A and of its direct regulator ACC might determine an unbalanced redox state and dictate the anti-tumor effect of the combination therapy in MYCN-amplified xenografts.