Treatment of tumor cells with the glycolytic inhibitor, 2-deoxy-D-glucose: Effects and mechanisms of resistance

Hypoxic regions within solid tumors harbor cells that are resistant to standard chemo- and radio-therapies. Since oxygen is required to produce ATP by oxidative phosphorylation, cells under hypoxia (anaerobic) rely on glycolysis to generate ATP. Thus, it was proposed that glycolytic inhibitors such as 2-deoxyglucose (2-DG) could be used to selectively target the hypoxic cell population within most solid tumors, while sparing the well-oxygenated, normal tissues (Liu et al., 2001; Liu et al., 2002). Here, in three distinct models of anaerobiosis, we show that 2-DG is, indeed, cytotoxic to anaerobically growing cells vs. their normoxically growing counterparts. These data supported our hypothesis that 2-DG would be effective as an adjunct therapy for human tumors, and helped initiate Phase I clinical trials (Feb 2004) using 2-DG in combination with docetaxel to target both the hypoxic, chemotherapy-resistant cells as well as the aerobic cells within solid tumors, respectively (Protocol # 2003121, A Phase I dose escalation trial of 2-deoxy-D-glucose (2-DG) alone and in combination with docetaxel in subjects with advanced solid malignancies ). We also demonstrated that activation of hypoxia-inducible factor-1 (HIF-1) mediates resistance to 2-DG treatment in hypoxic tumor cells, thereby suggesting that glycolytic inhibitors may be more clinically effective when combined with agents that inhibit this pathway. Additionally, we show that the surprising sensitivity of one pancreatic cancer cell line under normoxia correlates with both expression of GLUT-1 and uptake/retention of 2-DG. This suggests that evaluation of GLUT-1 expression and glucose uptake in pancreatic tumors may allow for identifying patients who could possibly benefit from single-agent 2-DG treatment. Overall, these studies indicate that administration of 2-DG could enhance current cancer treatment protocols by targeting hypoxic regions within solid tumors, and provide insight which may improve the clinical application of this agent in the future