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Int. J. Mol. Sci. 2018, 19(8), 2462; https://doi.org/10.3390/ijms19082462

Rescue of 2-Deoxyglucose Side Effects by Ketogenic Diet

1
Dr. Senckenberg Institute of Neurooncology, University Hospital Frankfurt, Goethe University, Schleusenweg 2-16, 60528 Frankfurt am Main, Germany
2
University Cancer Center Frankfurt (UCT), University Hospital Frankfurt, Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany
3
German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany
4
LOEWE Center for Personalized Translational Epilepsy Research (CePTER), University Hospital Frankfurt, Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany
5
Interdisciplinary Division of Neuro-Oncology, University Hospital Tübingen, Hoppe-Seyler-Straße 3, 72076 Tübingen, Germany
*
Author to whom correspondence should be addressed.
Received: 1 August 2018 / Revised: 13 August 2018 / Accepted: 15 August 2018 / Published: 20 August 2018
(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)
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Abstract

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. View Full-Text
Keywords: 2-deoxyglucose (2-DG); isocaloric ketogenic diet; glycolysis; Warburg effect; metabolic cancer therapy 2-deoxyglucose (2-DG); isocaloric ketogenic diet; glycolysis; Warburg effect; metabolic cancer therapy
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).
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Voss, M.; Lorenz, N.I.; Luger, A.-L.; Steinbach, J.P.; Rieger, J.; Ronellenfitsch, M.W. Rescue of 2-Deoxyglucose Side Effects by Ketogenic Diet. Int. J. Mol. Sci. 2018, 19, 2462.

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