Diaminobutoxy-substituted Isoflavonoid (DBI-1) Enhances the Therapeutic Efficacy of GLUT1 Inhibitor BAY-876 by Modulating Metabolic Pathways in Colon Cancer Cells

Cancer cells undergo significant "metabolic remodeling" to provide sufficient ATP to maintain cell survival and to promote rapid growth. In colorectal cancer cells, ATP is produced by mitochondria! oxidative phosphorylation and by substantially elevated cytoplasmic glucose fermentation (i.e., the Warburg effect). Glucose transporter 1 (GLUT]) expression is significantly increased in colorectal cancer cells, and GLUT1 inhibitors block glucose uptake and hence glycolysis crucial for cancer cell growth. In addition to ATP, these metabolic pathways also provide macro- molecule building blocks and signaling molecules required for tumor growth. In this study, we identify a diaminobutoxy-substituted isoflavonoid (DBI-1) that inhibits mitochondrial complex I and deprives rapidly growing cancer cells of energy needed for growth. DBI-1 and the GLUT1 inhibitor, BAY-876, synergistically inhibit colorectal cancer cell growth in vitro and in vivo. This study suggests that an electron transport chain inhibitor (i.e., DBI-1) and a glucose transport inhibitor, (i.e., BAY-876) are potentially effective combination for colorectal cancer treatment.