Increasing evidence suggests that
cancer cells (relative to normal cells) have altered mitochondrial electron transport chains (ETC) that are more likely to form
reactive oxygen species (ROS; i.e., O(2)(*-) and H(2)O(2)) resulting in a condition of chronic metabolic oxidative stress, that maybe compensated for by increasing
glucose and
hydroperoxide metabolism. In the current study, the ability of an inhibitor of
glucose metabolism,
2-deoxy-D-glucose (2DG), combined with mitochondrial electron transport chain blockers (ETCBs) to enhance oxidative stress and cytotoxicity was determined in human
colon cancer cells. Treatment of HT29 and HCT116
cancer cells with
Antimycin A (Ant A) or
rotenone (Rot) increased carboxy-dichlorodihydrofluorescein diacetate (
H2DCFDA) and
dihydroethidine (DHE) oxidation, caused the accumulation of
glutathione disulfide and enhanced 2DG-induced cell killing. In contrast, Rot did not enhance the toxicity of 2DG in normal human fibroblasts supporting the hypotheses that
cancer cells are more susceptible to inhibition of
glucose metabolism in the presence of ETCBs. In addition, 2-methoxy-antimycin A (Meth A; an analog of Ant A that does not have ETCB activity) did not enhance 2DG-induced DHE oxidation or cytotoxicity in
cancer cells. Finally, in HT29
tumor bearing mice treated with the combination of 2DG (500 mg/kg) + Rot (2 mg/kg) the average rate of
tumor growth was significantly slower when compared to control or either
drug alone. These results show that 2DG-induced cytotoxicity and oxidative stress can be significantly enhanced by ETCBs in human
colon cancer cells both in vitro and in vivo.