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Introduction
Cancer cells grow more rapidly than tumoral blood vessels (1). This characteristic of cancer cells induces an intra-tumoral hypoxia (2) that in turn decreases the growth of cancer cells. When cancer cell growth is decreased, so is the cell’s sensitivity to oncologic therapies (3,4).
Mammalian cells produce energy primarily by oxidative phosphorylation (OXPHOS) and to a lesser extent by glycolysis. Cancer cells have increased glucose transporters, glycolytic enzymes and the proteins that inhibit OXPHOS. As a result, cancer cells have high levels of glycolysis and low levels of OXPHOS. Therefore, cancer cells switch their primary pathway of energy production from OXPHOS to glycolysis. This phenomenon was first described by Warburg (5) and is known as the Warburg effect. Mechanisms of the Warburg effect are poorly defined and may involve the transcription factor hypoxia-inducible factor-1 (HIF-1) (6).
HIF-1 comprises α and β subunits (7). Upon biosynthesis, HIF-1α is hydroxylated in the presence of oxygen and is then degraded in proteasomes (8). Thus, normal mammalian cells have HIF-1β but not HIF-1α. When cells are subjected to hypoxia, however, HIF-1α is stabilized and associated with HIF-1β. Thus, intra-tumoral hypoxia appears to be causally responsible for HIF-1α expression that is seen in different cancer cells (6). In addition, cancer cells may have an increased HIF-1α production (9). When cancer cells produce more HIF-1α than they can degrade, HIF-1α is accumulated. HIF-1α expression increases glucose transporters, glycolytic enzymes, and the inhibitors of OXPHOS. Therefore, cancer-induced HIF-1α plays a key role in the Warburg effect (10–13).
As the first step of glycolysis, glucose is phosphorylated by hexokinase to produce glucose-6-phosphate (G-6-P). Next, G-6-P is converted to fructose-6-phosphate by phosphoglucose isomerase (PGI). In cancer cells, the predominant form of hexokinase is hexokinase-2 (HK-II) that is attached to the outer membrane of the mitochondria (12). Inhibition of HK-II not only decreases energy production but also impairs the mitochondria in cancer cells. Several HK-II inhibitors have been developed, including 2-deoxy-D-glucose (2-DG) and 3-bromopyruvate (3-BrPA) (14–25).
After 2-DG is transported in cancer cells by overexpressed glucose transporters, it is phosphorylated by HK-II to produce 2-DG-6-phosphate (2-DG-6-P). However, this product cannot be metabolized further, so it accumulates in cancer cells and inhibits HK-II by allosteric feedback. Meanwhile, non-phosphorylated 2-DG competes with glucose for binding to...