2DG enhances the susceptibility of breast cancer cells to doxorubicin

Abstract

2DG causes cytotoxicity in cancer cells by disrupting thiol metabolism while Doxorubicin (DOX) induces cytotoxicity in tumor cells by generating reactive oxygen species (ROS). Here we examined the combined cytotoxic action of 2DG and DOX in rapidly dividing T47D breast cancer cells vs. slowly growing MCF-7 breast cancer cells. T47D cells exposed to the combination of 2DG/DOX significantly decreased cell survival compared to controls, while 2DG/DOX had no effect on MCF-7 cells. 2DG/DOX also disrupted the oxidant status of T47D treated cells, decreased intracellular total glutathione and increased glutathione disulfide (%GSSG) compared to MCF-7 cells. Lipid peroxidation increased in T47D cells treated with 2DG and/or DOX, but not in MCF-7 cells. T47D cells were significantly protected by NAC, indicating that the combined treatment exerts its action by increasing ROS production and disrupting antioxidant stores. When we inhibited glutathione synthesis with BSO, T47D cells became more sensitive to 2DG/DOX-induced cytotoxicity, but NAC significantly reversed this cytotoxic effect. Finally, 2DG/DOX, and BSO significantly increased the %GSSG in T47D cells, an effect which was also reversed by NAC. Our results suggest that exposure of rapidly dividing breast cancer cells to 2DG/DOX enhances cytotoxicity via oxidative stress and via disruptions to thiol metabolism.

High Efficiency Apoptosis Induction in Breast Cancer Cell Lines by MLN4924/2DG Co-Treatment

“…These findings support previous studies on 2DG that was increased the effects of other chemotherapy drugs (DOX) and reduced the viability of breast cancer cell lines (Ahmad et al, 2010). But unlike previous studies, we did not find a very significant impact on the treatment of MCF7 cell lines by 2DG alone at 500 µM (Ahmad et al, 2010). We also observed a significant reduction in survival and apoptosis induction in SKBR-3 cells compared to MCF7 cells that treated with 2DG alone and the combination therapy.…”

“…It appears that that the combination treatment by the two drugs has a much stronger deleterious effect than either drug. These findings support previous studies on 2DG that was increased the effects of other chemotherapy drugs (DOX) and reduced the viability of breast cancer cell lines (Ahmad et al, 2010). But unlike previous studies, we did not find a very significant impact on the treatment of MCF7 cell lines by 2DG alone at 500 µM (Ahmad et al, 2010).…”

“…Studies have shown that 2DG increases the efficacy of other chemotherapeutics agents, for example (DOX and Pacitaxel) in human osteosarcoma and non-small cell lung cancers in vivo (Kern and Norton, 1987). Also, 2DG plus DOX and BSO significantly enhances cytotoxicity via oxidative stress and via disruptions to thiol metabolism in breast cancer cells (Ahmad et al, 2010). recently, the effort to discover small-molecule inhibitors against CRL/ SCF led to the discovery of MLN4924.…”

“…One of the biochemical characteristics related to the cancer cells is an increased utilization of glucose. The rate of glucose utilization in tumors is mostly correlated with the rate of proliferation and the degree of aggressiveness, thus cancer cells use more glucose than normal cells (Ahmad et al, 2010). Also, accelerated glucose uptake for aerobic glycolysis is one of the major metabolic changes found in malignant cells.…”

“…2DG changes N-linked glycosylation and lead s to unfolded protein responses and induces changes in gene expression and phosphorylation status of proteins involved in signaling, cell cycle control, DNA repair, Calcium influx and apoptosis (Dwarakanath, 2009). This leads to multiple related mechanisms which may involve in glucose-deprivation-induced signaling including the activation of kinases, changes in the redox state of the cell, or generation of free radicals (Zhang and Aft, 2009;Ahmad et al, 2010). Some studies in vitro have also shown that 2DG at non-toxic doses in combination with radiation therapy act as a radiosensitizer in various cancer cell types (Lin et al, 2003;Heminger et al, 2006;Dwarakanath, 2009).…”