Rescue of 2-Deoxyglucose Side Effects by Ketogenic Diet

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.

Acute Inflammation Alters Brain Energy Metabolism in Mice and Humans: Role in Suppressed Spontaneous Activity, Impaired Cognition, and Delirium

“…3 K ). On subjective examination, mice receiving 2-DG alone did not appear sick but those showing the lowest activity post-2-DG tended to be those showing the highest levels of glucose, perhaps suggesting that blocking glucose utilization (functionally similar to hypoglycemia) could increase blood glucose but still produce inactivity as has been shown with higher doses of 2-DG ( Voss et al, 2018 ).…”

Metabolism of pancreatic cancer: paving the way to better anticancer strategies

“…Some of the completed trials even showed promising and exciting results. Given the side effects of some metabolic regulators [219], the role of metabolism targeted therapy in nonmalignant tissues should also be emphasized in future research, which largely restricts the transformation from basic study to successful clinical application. Moreover, pancreatic cancer displayed highly plastic metabolism, suggesting that cancer cells can adapt to use other metabolic pathways to bypass a [220].…”

Natural Agents Targeting Mitochondria in Cancer

“…Recent research has focused on exploring those agents that can potentially inhibit the action of HKII, thereby inhibiting the function of glucose metabolism. For example, 2-deoxy- d -glucose (2-DG) and 3-bromopyruvate (3-BP) are the common synthetic mitocans that exhibit their cytotoxic effect on the cancer cells by inhibiting the HKII [ 63 , 64 ]. Benserazide is another mitocan that selectively inhibits HKII by specifically binding to HKII and inhibiting the enzymatic activity of HKII.…”