2-deoxy-D-Glucose Synergizes with Doxorubicin or L-Buthionine Sulfoximine to Reduce Adhesion and Migration of Breast Cancer Cells

Abstract

<b>Background:</b> Cancer metastasis depends on cell motility which is driven by cycles of actin polymerizationand depolymerization. Reactive oxygen species (ROS) and metabolic oxidative stress have long been associatedwith cancer. ROS play a vital role in regulating actin dynamics that are sensitive to oxidative modification. Thecurrent work aimed at studying the effects of sub-lethal metabolic oxidative stress on actin cytoskeleton, focaladhesion and cell migration. Materials and <br/><b>Methods</b>: T47D human breast cancer cells were treated with 2-deoxy-D-glucose (2DG), L-buthionine sulfoximine (BSO), or doxorubicin (DOX), individually or in combination, andchanges in intracellular total glutathione and malondialdehyde (MDA) levels were measured. The expressionof three major antioxidant enzymes was studied by immunoblotting, and cells were stained with fluorescentphalloidinto evaluate changes in F-actin organization. In addition, cell adhesion and degradation ability weremeasured. Cell migration was studied using wound healing and transwell migration assays. <br/><b>Results</b>: Our resultsshow that treating T47D human breast cancer cells with drug combinations (2DG/BSO, 2DG/DOX, or BSO/DOX)decreased intracellular total glutathione and increased oxidized glutathione, lipid peroxidation, and cytotoxicity.In addition, the drug combinations caused a reduction in cell area and mitotic index, prophase arrest and adecreased ability to form invadopodia. The formation of F-actin aggregates was increased in treated T47D cells.Moreover, combination therapy reduced cell adhesion and the rate of cell migration. <br/><b>Conclusions</b>: Our resultssuggest that exposure of T47D breast cancer cells to combination therapy reduces cell migration via effects onmetabolic oxidative stress.