Rescue of 2-Deoxyglucose Side Effects by Ketogenic Diet

International Journal of Molecular Sciences

MichaelW. Ronellenfitsch¹  Martin Voss¹  Anna-Luisa Luger¹  JoachimP. Steinbach¹  NadjaI. Lorenz¹  Johannes Rieger² 

[1] Dr. Senckenberg Institute of Neurooncology, University Hospital Frankfurt, Goethe University, Schleusenweg 2-16, 60528 Frankfurt am Main, Germany;Interdisciplinary Division of Neuro-Oncology, University Hospital Tübingen, Hoppe-Seyler-Straße 3, 72076 Tübingen, Germany;

关键词: 2-deoxyglucose (2-DG);    isocaloric ketogenic diet;    glycolysis;    Warburg effect;    metabolic cancer therapy;   

DOI  :  10.3390/ijms19082462

来源: DOAJ

【 摘 要 】

Cancer metabolism is characterized by extensive glucose consumption through aerobic glycolysis. No effective therapy exploiting this cancer trait has emerged so far, in part, due to the substantial side effects of the investigated drugs. In this study, we examined the side effects of a combination of isocaloric ketogenic diet (KD) with the glycolysis inhibitor 2-deoxyglucose (2-DG). Two groups of eight athymic nude mice were either fed a standard diet (SD) or a caloric unrestricted KD with a ratio of 4 g fat to 1 g protein/carbohydrate. 2-DG was investigated in commonly employed doses of 0.5 to 4 g/kg and up to 8 g/kg. Ketosis was achieved under KD (ketone bodies: SD 0.5 ± 0.14 mmol/L, KD 1.38 ± 0.28 mmol/L, p < 0.01). The intraperitoneal application of 4 g/kg of 2-DG caused a significant increase in blood glucose, which was not prevented by KD. Sedation after the 2-DG treatment was observed and a behavioral test of spontaneous motion showed that KD reduced the sedation by 2-DG (p < 0.001). A 2-DG dose escalation to 8 g/kg was lethal for 50% of the mice in the SD and for 0% of the mice in the KD group (p < 0.01). A long-term combination of KD and an oral 1 or 2 g 2-DG/kg was well-tolerated. In conclusion, KD reduces the sedative effects of 2-DG and dramatically increases the maximum tolerated dose of 2-DG. A continued combination of KD and anti-glycolytic therapy is feasible. This is, to our knowledge, the first demonstration of increased tolerance to glycolysis inhibition by KD.

【 授权许可】

Unknown