2-Deoxy-d-glucose Increases the Efficacy of Adriamycin and Paclitaxel in Human Osteosarcoma and Non-Small Cell Lung Cancers In Vivo

Abstract

Slow-growing cell populations located within solid tumors are difficult to target selectively because most cells in normal tissues also have low replication rates. However, a distinguishing feature between slow-growing normal and tumor cells is the hypoxic microenvironment of the latter, which makes them extraordinarily dependent on anaerobic glycolysis for survival. Previously, we have shown that hypoxic tumor cells exhibit increased sensitivity to inhibitors of glycolysis in three distinct in vitro models. Based on these results, we predicted that combination therapy of a chemotherapeutic agent to target rapidly dividing cells and a glycolytic inhibitor to target slow-growing tumor cells would have better efficacy than either agent alone. Here, we test this strategy in vivo using the glycolytic inhibitor 2-deoxy-D-glucose (2-DG) in combination with Adriamycin (ADR) or paclitaxel in nude mouse xenograft models of human osteosarcoma and non-small cell lung cancer. Nude mice implanted with osteosarcoma cells were divided into four groups as follows: (a) untreated controls; (b) mice treated with ADR alone; (c) mice treated with 2-DG alone; or (d) mice treated with a combination of ADR ؉ 2-DG. Treatment began when tumors were either 50 or 300 mm 3 in volume. Starting with small or large tumors, the ADR ؉ 2-DG combination treatment resulted in significantly slower tumor growth (and therefore longer survival) than the control, 2-DG, or ADR treatments (P < 0.0001). Similar beneficial effects of combination treatment were found with 2-DG and paclitaxel in the MV522 non-small cell lung cancer xenograft model. In summary, the treatment of tumors with both the glycolytic inhibitor 2-DG and ADR or paclitaxel results in a significant reduction in tumor growth compared with either agent alone. Overall, these results, combined with our in vitro data, provide a rationale for initiating clinical trials using glycolytic inhibitors in combination with chemotherapeutic agents to increase their therapeutic effectiveness.

Hypoxia-inducible factor-1 confers resistance to the glycolytic inhibitor 2-deoxy-d-glucose

“…Thus, addition of glycolytic inhibitors to current cancer therapies should increase their efficacies by preferentially targeting this hypoxic, slow-growing tumor cell population. In fact, 2-DG treatment was found to significantly enhance the ability of both Adriamycin and cisplatin to reduce the tumor volume of human osteosarcoma and non -small cell lung cancer cells growing in nude mice (7). These data correlate with a previous study in which it was shown that 2-DG in combination with an experimental anticancer agent dinaline showed increased antitumor efficacy (8).…”

Glucose Withdrawal Induces Oxidative Stress followed by Apoptosis in Glioblastoma Cells but not in Normal Human Astrocytes

“…As such, inhibitors of glycolysis including 3-bromopyruvate and 5-thioglucose provide promising therapeutic strategies (12,36). These inhibitors of glycolysis stand in contrast to 2DG, an inhibitor of glycolysis that has been advanced by other investigators as a potential therapeutic approach (25,37,38). Our results indicate a danger in using 2DG as an anticancer therapy because treatment with 2DG in the setting of glucose withdrawal prevented rather than promoted cell death.…”

Synergistic effect of targeting mTOR by rapamycin and depleting ATP by inhibition of glycolysis in lymphoma and leukemia cells

“…For instance, several glycolytic inhibitors that target key glycolytic enzymes have been tested for their anticancer activity in vitro and in vivo. [4][5][6][7][8] Such a metabolic intervention seems to produce encouraging results, at least in experimental model systems.…”