title: Radiosensitization by 2-deoxy-D-glucose and 6-aminonicotinamide involves activation of redox sensitive ASK1-JNK/p38MAPK signaling in head and neck cancer cells.
abstract: Our previous studies on simultaneous inhibition of glycolysis by 2-deoxy-D-glucose (2-DG) and pentose phosphate activity by 6-aminonicotinamide (6-AN) have been shown to induce oxidative stress mediated selective radiosensitization in wide range of human malignant cells. However, the mechanism of radiosensitization induced by this combination (2-DG+6-AN) is not completely understood. Since activation of apoptotic signal regulating kinase (ASK1) and subsequent apoptosis are implicated in oxidative stress response, the role of ASK1 activation in radiosensitization by this combination was investigated in the present study. Our results demonstrated that redox alterations induced by this combination activated ASK1 and subsequent apoptosis during radiosensitization of head and neck carcinoma cells (KB). In addition, mRNA and protein expression of thioredoxin and thioredoxin reductase decreased significantly under similar treatment conditions. Further, the downstream targets such as JNK and p38MAPK were also activated by this combination, and their pharmacological inhibition by SP600125 and SB201291 respectively resulted in suppression of 2-DG+6-AN mediated apoptosis in irradiated KB cells. Interestingly, the activation of ASK1 was mediated by hydrogen peroxide rather than superoxide anions as PEG-catalase but not PEG-SOD suppressed its activation. Our observations clearly suggest that redox alterations by inhibition of glucose metabolism serves as a molecular switch that activate ASK1-JNK/p38MAPK signaling in malignant cells during radiosensitization by 2-DG+6-AN. The present study emphasizes the importance of redox alterations in determining radiosensitivity of tumor cells that may greatly influence the outcome of radiation therapy.
authors: Institute of Nuclear Medicine and Allied Sciences, DRDO, Brig. S K Mazumdar Road, Delhi-110 054, India.
authors: Pradeep Kumar
authors: PK
authors: Sharma
authors: Bilikere Srinivasa
authors: BS
authors: Dwarakanath
authors: Rajeev
authors: R
authors: Varshney
mesh_terms: D015120:6-Aminonicotinamide / Q000494:pharmacology*; D017209:Apoptosis; D002294:Carcinoma, Squamous Cell; D049109:Cell Proliferation; D003847:Deoxyglucose / Q000494:pharmacology*; D004357:Drug Synergism; D005720:Gamma Rays; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism*; D048848:MAP Kinase Kinase Kinase 5 / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D011836:Radiation Tolerance; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D000077195:Squamous Cell Carcinoma of Head and Neck; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D011838:Radiation-Sensitizing Agents; D017382:Reactive Oxygen Species; D015120:6-Aminonicotinamide; D003847:Deoxyglucose; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; C482858:MAP3K5 protein, human; D048670:MAP Kinase Kinase 4