Differential toxic mechanisms of 2-deoxy-D-glucose versus 2-fluorodeoxy-D-glucose in hypoxic and normoxic tumor cells.
The dependence of hypoxic tumor cells on glycolysis as their main means of producing ATP provides a selective target for agents that block this pathway, such as 2-deoxy-D-glucose (2-DG) and 2-fluoro-deoxy-D-glucose (2-FDG). Moreover, it was demonstrated that 2-FDG is a more potent glycolytic inhibitor with greater cytotoxic activity than 2-DG. This activity correlates with the closer structural similarity of 2-FDG to glucose than 2-DG, which makes it a better inhibitor of hexokinase, the first enzyme in the glycolytic pathway. In contrast, because of its structural similarity to mannose, 2-DG is known to be more effective than 2-FDG in interfering with N-linked glycosylation. Recently, it was reported that 2-DG, at a relatively low dose, is toxic to certain tumor cells, even under aerobic conditions, whereas 2-FDG is not. These results indicate that the toxic effects of 2-DG in selected tumor cells under aerobic conditions is through inhibition of glycosylation rather than glycolysis. The intention of this minireview is to discuss the effects and potential clinical impact of 2-DG and 2-FDG as antitumor agents and to clarify the differential mechanisms by which these two glucose analogues produce toxicity in tumor cells growing under anaerobic or aerobic conditions.
Kurtoglu
Metin
M
University of Miami, Miller School of Medicine and Sylvester Cancer Center, Miami, Florida 33136, USA.
Maher
Johnathan C
JC
Lampidis
Theodore J
TJ
D000693:Anaerobiosis; D015687:Cell Hypoxia / Q000502:physiology*; D003847:Deoxyglucose / Q000633:toxicity*; D006019:Glycolysis; D006801:Humans; D008954:Models, Biological; D009369:Neoplasms / Q000473:pathology / Q000503:physiopathology*; D010101:Oxygen Consumption / Q000187:drug effects
D003847:Deoxyglucose