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 mitochondrial oxidative phosphorylation and by substantially elevated cytoplasmic
glucose fermentation (i.e., the Warburg effect).
Glucose transporter 1 (GLUT1) 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 macromolecule 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.