Glucose deprivation-induced oxidative stress and cancer therapy.

摘要

Most cancer cells demonstrate increased rates of glucose metabolism when compared to normal cells. Glucose metabolism leads to the formation of pyruvate and NADPH both of which function in the cellular detoxification of hydroperoxides. Therefore, tumor cells may increase their metabolism of glucose as a compensatory mechanism to protect against hydroperoxides generated as byproducts of mitochondrial metabolism. Recent studies have shown that glucose deprivation preferentially induces cytotoxicity and oxidative stress in human cancer cells, relative to normal cells. If differential sensitivity to glucose deprivation-induced oxidative stress were a common feature of cancer cells, then combining 2-deoxyglucose (2DG) with agents that increase reactive oxygen species (ROS) (i.e ., wild type p53) would be predicted to dramatically sensitized tumor cells to cell killing relative to normal cells. Furthermore, if tumor cells utilize glucose to compensate for an oxidative metabolic defect, then the extent to which glucose utilization is increased should be proportional to tumor cell susceptibility to 2DG combined with wild type p53. The current research tested the following hypotheses: (1) Mitochondrial O₂ ·− and H₂O₂ mediate glucose deprivation-induced cytotoxicity and oxidative stress in human cancer cells. (2) The extent to which human tumor cells increase their metabolism of glucose is predictive of tumor cell susceptibility to therapy that is based on inhibiting glucose metabolism and increasing steady-state levels of hydroperoxides. The long-term goal was to determine the mechanism by which glucose deprivation-induced cytotoxicity and oxidative stress occurs in human cancer cells and to use FDG-PET imaging as a tool to predict which cancers are more susceptible to therapy that is based on inhibiting glucose metabolism and increasing steady state levels of hydroperoxides.; The results of these studies provide strong support for the hypothesis that mitochondrial O₂·− and H ₂O₂ contribute to glucose deprivation-induced cytotoxicity in human cancer cells. Furthermore, our results provide proof of principle data to support the hypothesis that measurements of glucose utilization may be useful in predicting sensitivity of tumor cells to combination therapies involving 2DG and wtp53 in vitro and in vivo.