Rescue of 2-Deoxyglucose Side Effects by Ketogenic Diet.

Martin Voss,Johannes Rieger,Anna-Luisa Luger,Nadja I Lorenz,Michael W Ronellenfitsch,Joachim P Steinbach

doi:10.3390/ijms19082462

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.

Highlights

We examined the side effects of a combination of isocaloric ketogenic diet (KD) with the glycolysis inhibitor 2-deoxyglucose (2-DG)
A key feature of malignant tumors and a hallmark of cancer is a change in metabolism [1], for example, glioblastomas (GBs), the most common malignant brain tumor in adults, and other cancers display elevated glycolysis even in the presence of oxygen
Glycolysis is blocked after the intracellular phosphorylation of 2-DG by hexokinase (Figure 1), which leads to ATP depletion and the activation of AMP-activated protein kinase (AMPK) [5,6,7]

Summary

Introduction

A key feature of malignant tumors and a hallmark of cancer is a change in metabolism [1], for example, glioblastomas (GBs), the most common malignant brain tumor in adults, and other cancers display elevated glycolysis even in the presence of oxygen (aerobic glycolysis) This effect was first described by Otto Warburg [2]. 2-DG induces the neuronal commitment of tumor cells [9], inhibits HIF-1α [10] as well as N-linked glycosylation [11], and sensitizes tumors cells to radiation therapy and chemotherapy [12] Despite these promising effects in vitro, 2-DG as a monotherapy failed to show a significant antitumor effect in many in vivo experiments in mice and patients, and 2-DG was established as a laboratory tool but not as an anti-cancer drug. To enhance the antitumor effect of 2-DG, it could be required to reduce the reactive hyperglycemia and turn the ratio in favor of 2-DG

Objectives

Methods

Results