Abstract
Tumor cells subjected to hypoxia and/or containing mitochondrial deficiencies rely mainly on glycolysis for energy production and consequently, glycolytic inhibition in such cells results in cell death. This rational lead to the hypothesis that glycolytic inhibitors such as 2-deoxy-D-glucose (2-DG) may be effectively used to target the hypoxic regions within solid tumors. In the first part of the thesis, it is demonstrated that 2-fluoro-deoxy-D-glucose (2-FDG) is a more potent glycolytic inhibitor with greater cytotoxic activity than 2-DG. This finding is based on the closer structural similarity of 2FDG to glucose than 2-DG making it a better inhibitor of hexokinase, the first enzyme in the glycolytic pathway. In contrast, due to its structural similarity to mannose, 2-DG is known to be more effective than 2-FDG in interfering with N-linked glycosylation. Thus, the second part of the thesis focuses on investigating the molecular pathways to explain how interference with N-linked glycosylation by 2-DG can induce cell death in certain tumor types growing in the presence of oxygen. Overall, the intention of this thesis 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 analogs produce toxicity in tumor cells growing under anaerobic or aerobic conditions.