Differential cytotoxicity of the glycolytic inhibitor 2-deoxy-D-glucose in isogenic cell lines varying in their p53 status

Earlier studies have shown that cytotoxicity of glycolic inhibitor 2-deoxy-D-glucose is heterogeneous among different tumor cell lines due to a number of reasons including difference in p53 status. To investigate the cytotoxic effects of 2-DG in isogenic cell systems that differ in their p53 status....

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Published in:	Journal of cancer research and therapeutics Vol. 9; no. 4; pp. 686 - 692
Main Authors:	Vibhuti, Archana, Muralidhar, Kambadur, Dwarakanath, Bilikere S
Format:	Journal Article
Language:	English
Published:	India Medknow Publications and Media Pvt. Ltd 01-10-2013 Medknow Publications & Media Pvt. Ltd
Subjects:	Annexin A5 - metabolism Antimetabolites - pharmacology Apoptosis Apoptosis - drug effects Cancer Carcinoma, Squamous Cell - drug therapy Carcinoma, Squamous Cell - genetics Cell culture Cell Cycle - drug effects Cell Line, Tumor Cell Proliferation - drug effects Cell Survival - drug effects Colony-Forming Units Assay Cytotoxicity Dehydrogenases Deoxyglucose - pharmacology Deoxyribonucleic acid Dextrose DNA Enzymes Gene expression Glucose Glycolysis - drug effects Head & neck cancer Head and Neck Neoplasms - drug therapy Head and Neck Neoplasms - genetics Humans Identification and classification Kinases Metabolism Mutation NADP - metabolism Oncology, Experimental Oxidative stress Oxidative Stress - drug effects Phosphorylation Physiological aspects Protein Binding - drug effects Proteins Reactive Oxygen Species Rodents Squamous Cell Carcinoma of Head and Neck Transcription factors Tumor Suppressor Protein p53 - genetics Tumors
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Summary:	Earlier studies have shown that cytotoxicity of glycolic inhibitor 2-deoxy-D-glucose is heterogeneous among different tumor cell lines due to a number of reasons including difference in p53 status. To investigate the cytotoxic effects of 2-DG in isogenic cell systems that differ in their p53 status. Head and neck carcinoma cells KB and its two p53 mutants (KB68-mutation in transactivation domain (Arg/Cys) at position 68 and KB110-mutation in proline rich deoxyribonucleic acid binding domain (Glu/Gly) at position 110) were used as the model. Clonogenecity, cell proliferation, cell cycle, annexin V assay, intracellular levels of ROS and NADP+/NADPH levels were investigated as parameters for 2-DG induced cytotoxicity. Macrocolony assay showed that the cytotoxicity of 2-DG was time- and concentration-dependent. However, the sensitivity of the three cell lines were quantitatively different, with KB110 being more sensitive than the parental cell line KB and KB68. The effects of 2-DG on growth inhibition, cell cycle, and apoptosis correlated well with the changes in cell survival in these cells. A higher degree of 2-DG induced enhancement in the metabolic oxidative stress was evident in both the mutant cell lines (elevated ROS level and NADP+/NADPH ratio) suggestive of a higher degree of compromize in the antioxidant defense in the mutant cells. 2-DG could be considered as a potential therapeutic agent that induces cell death (which could be linked to induced oxidative stress) selectively in tumors with p53 mutations (particularly in the proline rich region).
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0973-1482 1998-4138
DOI:	10.4103/0973-1482.126484