Cancer cells (relative to normal cells) demonstrate alterations in oxidative metabolism characterized by increased steady-state levels of
reactive oxygen species (i.e.,
hydrogen peroxide, H(2)O(2)) that may be compensated for by increased
glucose metabolism, but the therapeutic significance of these observations is unknown. In this study, inhibitors of
glucose (i.e., 2-deoxy-d-glucose, 2DG) and
hydroperoxide (i.e., l-
buthionine-S,R-sulfoximine, BSO) metabolism were utilized in combination with a chemotherapeutic agent,
paclitaxel (PTX), thought to induce oxidative stress, to treat
breast cancer cells. 2DG + PTX was more toxic than either agent alone in T47D and MDA-MB231 human
breast cancer cells, but not in normal human fibroblasts or normal human mammary epithelial cells. Increases in parameters indicative of oxidative stress, including steady-state levels of H(2)O(2), total
glutathione, and
glutathione disulfide, accompanied the enhanced toxicity of 2DG + PTX in
cancer cells.
Antioxidants, including
N-acetylcysteine and
polyethylene glycol-conjugated
catalase and
superoxide dismutase, inhibited the toxicity of 2DG + PTX and suppressed parameters indicative of oxidative stress in
cancer cells, whereas inhibition of
glutathione synthesis using BSO further sensitized
breast cancer cells to 2DG + PTX. These results show that combining inhibitors of
glucose (2DG) and
hydroperoxide (BSO) metabolism with PTX selectively (relative to normal cells) enhances
breast cancer cell killing via H(2)O(2)-induced metabolic oxidative stress, and suggest that this biochemical rationale may be effectively utilized to treat breast
cancers.