Co-treatment of breast cancer cells with pharmacologic doses of 2-deoxy-D-glucose and metformin: Starving tumors

Abstract

A characteristic of tumor cells is the increased aerobic glycolysis for energy production. Thus, inhibition of glycolysis represents a selective therapeutic option. It has been shown that glycolysis inhibitor 2-deoxy-D-glucose (2DG) induces apoptotic cell death in different tumor entities. In addition, the antitumor activity of the anti-diabetic drug metformin has been demonstrated. In the present study, we aimed to ascertain whether the combination of pharmacologic doses of 2DG with metformin increases the antitumor efficacy. Cell viability of MDA-MB-231 and HCC1806 triple-negative breast cancer (TNBC) cells treated without or with 2DG or with metformin alone or with the combination of both agents was measured using Alamar Blue assay. Induction of apoptosis was quantified by measurement of the loss of mitochondrial membrane potential and cleavage of PARP. Treatment of breast cancer cells with glycolysis inhibitor 2DG or with the anti-diabetic drug metformin resulted in a significant decrease in cell viability and an increase in apoptosis. Treatment with 2DG in combination with metformin resulted in significantly reduced viability compared with the single agent treatments. The observed reduction in viability was due to induction of apoptosis. In addition, in regards to apoptosis induction a stronger effect in the case of co-treatment compared with single agent treatments was observed. The glycolytic phenotype of human breast cancer cells can be targeted for therapeutic intervention. Co-treatment with doses of the glycolysis inhibitor 2DG and anti-diabetic drug metformin is tolerable in humans and may be a suitable therapy for human breast cancers.

Metabolic characterization of aggressive breast cancer cells exhibiting invasive phenotype: Impact of non-cytotoxic doses of 2-DG on diminishing invasiveness

“…Such INV showed upregulation of glucose uptake, and were effectively targeted using a glycolysis inhibitor, 2-DG. Several earlier studies have shown the ability of 2-DG to block cancer growth (12)(13)(14)(15)(47)(48). However, many of the clinical trials using 2-DG were discontinued due to the adverse side effects caused by the high doses of 2-DG (47,49).…”

“…2-deoxy-D-glucose (2-DG), a D-glucose mimetic, inhibits glycolysis due to formation and intracellular accumulation of 2-deoxy-D-glucose-6-hosphate, inhibiting the function of hexokinase and glucose-6-phosphate isomerase (10)(11). 2-DG has a potential application as an adjuvant for improving cancer therapy, as it was to be able to reduce cancer cell viability (12)(13)(14)(15), and also assessed in several clinical studies as an anticancer agent (16)(17)(18). However, clinical use of 2-DG still has been carefully studied because of its side effects (14,19).…”

GLUT1 inhibition blocks growth of RB1-positive Triple Negative Breast Cancer

“…Thus, glutamine deprivation sensitizes the resistant cells to BAY-876 inhibition. This synergism between glycolysis inhibitors combined with OXPHOS inhibition suggests a strong rationale using two or more drugs targeting different metabolic pathways to achieve superior therapeutic benefits for TNBC treatment 56,57 .…”

Metabolic characterization of aggressive breast cancer cells exhibiting invasive phenotype: Impact of non-cytotoxic doses of 2-DG on diminishing invasiveness

“…We rst con rmed that treatment of cells with 0.3 or 1 mM 2-DG for 16 h reduced lactate production by SUM149, MDA-MB-231, and HCC1937 cell lines (Supplemental Figure 8), suggesting that low concentration of 2-DG was su cient to reduce glycolysis. Inhibition of glycolysis is known to reduce cell viability (12)(13)(14)(15). Thus, we next investigated the sensitivity of SUM149, MDA-MB-231, or HCC1937 to same concentrations of 2-DG ( Figure 6A-C).…”

“…2-deoxy-D-glucose (2-DG), a D-glucose mimetic, inhibits glycolysis due to formation and intracellular accumulation of 2-deoxy-D-glucose-6-phosphate, inhibiting the function of hexokinase and glucose-6-phosphate isomerase (10)(11). 2-DG has a potential application as an adjuvant for improving cancer therapy, as it was to be able to reduce cancer cell viability (12)(13)(14)(15) and has also been assessed in several clinical studies as an anticancer agent (16)(17)(18). However, clinical use of 2-DG still has been carefully studied because of its side effects (14,19).…”