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Rescue of 2-Deoxyglucose Side Effects by Ketogenic Diet.
- Source :
-
International journal of molecular sciences [Int J Mol Sci] 2018 Aug 20; Vol. 19 (8). Date of Electronic Publication: 2018 Aug 20. - Publication Year :
- 2018
-
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.
- Subjects :
- Animals
Antimetabolites administration & dosage
Blood Glucose metabolism
Deoxyglucose administration & dosage
Female
Glucose metabolism
Glycolysis drug effects
Ketone Bodies metabolism
Ketosis etiology
Ketosis metabolism
Mice, Nude
Neoplasms metabolism
Antimetabolites adverse effects
Deoxyglucose adverse effects
Diet, Ketogenic methods
Subjects
Details
- Language :
- English
- ISSN :
- 1422-0067
- Volume :
- 19
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- International journal of molecular sciences
- Publication Type :
- Academic Journal
- Accession number :
- 30127309
- Full Text :
- https://doi.org/10.3390/ijms19082462