title: Metabolic oxidative stress induced by a combination of 2-DG and 6-AN enhances radiation damage selectively in malignant cells via non-coordinated expression of antioxidant enzymes.
abstract: Our earlier studies have shown that simultaneous inhibition of glycolysis and pentose phosphate pathway using 2-deoxy-d-glucose (2-DG, an inhibitor of glycolysis) and 6-aminonicotinamide (6-AN, an inhibitor of pentose phosphate pathway) lead to metabolic oxidative stress (MOS), resulting in radiosensitization in malignant cells. Present study was carried out to investigate the effects of 2-DG and 6-AN on intricately regulated endogenous antioxidant defense against MOS during radiosensitization by this combination. Two human tumor cell lines {Head and Neck Squamous carcinoma (KB) and Glioma (BMG-1)} and one non-malignantly transformed cell line (human embryonic kidney, HEK) were used in this study. The presence of 2-DG and 6-AN (added just before irradiation) for 4h, significantly decreased the clonogenicity and metabolic viability of KB and BMG-1 cell lines, while no significant change was seen in HEK cells. Accumulation of ROS was observed only in malignant cell lines, which displayed a compromised redox status evident from enhanced NADP(+)/NADPH and GSSG/GSH ratios and a concomitant decrease in glutathione reductase level and activity at 24h following treatment. The levels and activities of Cu, Zn-SOD and Mn-SOD increased with MOS and were accompanied by a decreased GPx and unaltered catalase activity and level. These results suggest that non-coordinated expression of antioxidant defense, besides compromised redox status, led to selective radiosensitization in the malignant cells.
authors.affiliation: Institute of Nuclear Medicine and Allied Sciences, Delhi, India.
authors.forename: Pradeep K
authors.initials: PK
authors.lastname: Sharma
authors.forename: Richa
authors.initials: R
authors.lastname: Bhardwaj
authors.forename: Bilikere S
authors.initials: BS
authors.lastname: Dwarakanath
authors.forename: Rajeev
authors.initials: R
authors.lastname: Varshney
mesh_terms: D015120:6-Aminonicotinamide / Q000494:pharmacology*; D000975:Antioxidants / Q000378:metabolism*; D002374:Catalase / Q000378:metabolism; D045744:Cell Line, Tumor; D003847:Deoxyglucose / Q000494:pharmacology*; D005978:Glutathione / Q000032:analysis; D005979:Glutathione Peroxidase / Q000378:metabolism; D005980:Glutathione Reductase / Q000378:metabolism; D006801:Humans; D009249:NADP / Q000032:analysis; D009369:Neoplasms / Q000532:radiotherapy*; D018384:Oxidative Stress; D011836:Radiation Tolerance; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D000975:Antioxidants; D015120:6-Aminonicotinamide; D009249:NADP; D003847:Deoxyglucose; D002374:Catalase; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D005980:Glutathione Reductase; D005978:Glutathione