Increased levels of superoxide and H2O2 mediate the differential susceptibility of cancer cells versus normal cells to glucose deprivation
- 28 January 2009
- journal article
- research article
- Published by Portland Press Ltd. in Biochemical Journal
- Vol. 418 (1), 29-37
- https://doi.org/10.1042/bj20081258
Abstract
Cancer cells, relative to normal cells, demonstrate increased sensitivity to glucose-deprivation-induced cytotoxicity. To determine whether oxidative stress mediated by O2•− and hydroperoxides contributed to the differential susceptibility of human epithelial cancer cells to glucose deprivation, the oxidation of DHE (dihydroethidine; for O2•−) and CDCFH2 [5- (and 6-)carboxy-2′,7′-dichlorodihydrofluorescein diacetate; for hydroperoxides] was measured in human colon and breast cancer cells (HT29, HCT116, SW480 and MB231) and compared with that in normal human cells [FHC cells, 33Co cells and HMECs (human mammary epithelial cells)]. Cancer cells showed significant increases in DHE (2–20-fold) and CDCFH2 (1.8–10-fold) oxidation, relative to normal cells, that were more pronounced in the presence of the mitochondrial electron-transport-chain blocker, antimycin A. Furthermore, HCT116 and MB231 cells were more susceptible to glucose-deprivation-induced cytotoxicity and oxidative stress, relative to 33Co cells and HMECs. HT29 cells were also more susceptible to 2DG (2-deoxyglucose)-induced cytotoxicity, relative to FHC cells. Overexpression of manganese SOD (superoxide dismutase) and mitochondrially targeted catalase significantly protected HCT116 and MB231 cells from glucose-deprivation-induced cytotoxicity and oxidative stress and also protected HT29 cells from 2DG-induced cytotoxicity. These results show that cancer cells (relative to normal cells) demonstrate increased steady-state levels of ROS (reactive oxygen species; i.e. O2•− and H2O2) that contribute to differential susceptibility to glucose-deprivation-induced cytotoxicity and oxidative stress. These studies support the hypotheses that cancer cells increase glucose metabolism to compensate for excess metabolic production of ROS and that inhibition of glucose and hydroperoxide metabolism may provide a biochemical target for selectively enhancing cytotoxicity and oxidative stress in human cancer cells.This publication has 38 references indexed in Scilit:
- Enhanced Response of Human Head and Neck Cancer Xenograft Tumors to Cisplatin Combined With 2-Deoxy-d-Glucose Correlates With Increased 18F-FDG Uptake as Determined by PET ImagingInternational Journal of Radiation Oncology*Biology*Physics, 2007
- 2-Deoxy-d-Glucose Combined with Cisplatin Enhances Cytotoxicity via Metabolic Oxidative Stress in Human Head and Neck Cancer CellsCancer Research, 2007
- Inhibition of Glutamate Cysteine Ligase Activity Sensitizes Human Breast Cancer Cells to the Toxicity of 2-Deoxy-d-GlucoseCancer Research, 2006
- Facile Detection of Mitochondrial DNA Mutations in Tumors and Bodily FluidsScience, 2000
- Metabolic oxidative stress activates signal transduction and gene expression during glucose deprivation in human tumor cellsFree Radical Biology & Medicine, 1999
- Redox Gene Therapy Protects Human IB-3 Lung Epithelial Cells Against Ionizing Radiation-Induced ApoptosisHuman Gene Therapy, 1998
- Glucose Deprivation-induced Cytotoxicity and Alterations in Mitogen-activated Protein Kinase Activation Are Mediated by Oxidative Stress in Multidrug-resistant Human Breast Carcinoma CellsOnline Journal of Public Health Informatics, 1998
- The mitochondrial site of superoxide formationBiochemical and Biophysical Research Communications, 1986
- Enzymology of Cancer CellsThe New England Journal of Medicine, 1977
- On the Origin of Cancer CellsScience, 1956