{Author 1 (Prefix):11.2} {Author 1 (Last):11.6}

TitelKetogenic diet and metformin enhance the effect of cyclophosphamide on Neuroblastoma
Einleitung

Neuroblastoma (NB) is a childhood cancer within a subgroup of high-risk patients. The MYCN amplification is the most acknowledged marker of poor NB prognosis. Previously we revealed that a low carbohydrate, high fat ketogenic diet (KD) successfully targets NB, especially when combined with classical cytotoxic therapy cyclophosphamide (CP). Recent findings have suggested that the inhibition of residual oxidative phosphorylation (OXPHOS) activity could be beneficial for cancer treatment. 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 effect of low dose of CP therapy.

Patient/en und Methoden

A quantitative measure of mitochondrial function using Oxygen consumption rate (OCR) was measured by Agilent Seahorse XF Analyzer. NB xenografts were established in CD-1 nude mice with the Myc-N amplified cell lines SKNBE(2) and KELLY. The NB-bearing mice were fed with a control diet (CTRL) or a KD (ketogenic ratio 8:1, supplemented with medium-chain triglycerides) with/without MET (oral gavage, 100 mg/kg body weight) and with/without low-dose cyclophosphamide (CP) 13 mg/kg in SKNBE(2) xenografts and 20 mg/kg for KELLY xenografts, in drinking water. Microbiome analysis of feces was performed by qRT-PCR. 20 different biomarkers potentially involved in tumor progression were measured in plasma by Mesoscale Discovery Technology.

Ergebnisse

Maximal mitochondrial respiration was inhibited by MET (doses from 1 mM to 10 mM) in the MYCN amplified NB cells. MET enhanced the anti-proliferative effect of the KD when combined with CP. The triple therapy (MET+CP+KD) also led to an increase of survival when compared to CP + CTRL diet in both xenografts models. The KD-induced elevation of ketone bodies was not influenced by co-treatment with MET, while blood glucose levels were reduced in the KD + CP + MET groups. Fibroblast growth factor 21 (FGF-21) was highest in MET+CP+KD compared to all other treatment group. Lactobacillus levels were reduced in all KD groups. Clostridium cluster IV level was only reduced in groups treated with MET in combination with the KD.

Schlussfolgerung/Diskussion

Our data suggest that MET and KD can enhance the anti-tumor efficacy of chemotherapy and points to potentially novel adjuvant therapy opportunities.

Autor*in 1Luca Catalano Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical University, Salzburg, Austria;
Autor*in 2Sepideh Aminzadeh-Gohari Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical University, Salzburg, Austria;
Autor*in 3Daniela Weber Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical University, Salzburg, Austria;
Autor*in 4Rene Feichtinger Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical University, Salzburg, Austria;
Autor*in 5Silvia Vidali Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical University, Salzburg, Austria;
Autor*in 6William Smiles Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical University, Salzburg, Austria;
Autor*in 7Stefan Bereswill Charité - Institute for Micorbiology and Infectionimmunology, Berlin, Germany
Autor*in 8Barbara Kofler Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical University, Salzburg, Austria;