Paclitaxel combined with inhibitors of glucose and hydroperoxide metabolism enhances breast cancer cell killing via H2O2-mediated oxidative stress.

摘要

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.