Washington University in St. Louis

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Metabolomics to elucidate novel biochemical mechanisms of disease
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Radio-Resistant Cervical Cancers are Sensitive to Inhibition of Glycolysis and Redox Metabolism

Ramachandran R, Huang X, Floberg J, Elhamalli AE, McCormick ML, Patti GJ, Spitz DR, and Schwarz JK
Radio-Resistant Cervical Cancers are Sensitive to Inhibition of Glycolysis and Redox Metabolism
Cancer Research, 78(6), 1392-1403, 2018
doi:10.1158/0008-5472.CAN-17-2367

Highly glycolytic cervical cancers largely resist treatment by cisplatin and coadministered pelvic irradiation as the present standard of care. In this study, we investigated the effects of inhibiting glycolysis and thiol redox metabolism to evaluate them as alternate treatment strategies in these cancers. In a panel of multiple cervical cancer cell lines, we evaluated sensitivity to inhibition of glycolysis (2-deoxyglucose, 2-DG) with or without simultaneous inhibition of glutathione and thioredoxin metabolism (BSO/AUR). Intracellular levels of total and oxidized glutathione, thioredoxin reductase activity, and indirect measures of intracellular reactive oxygen species were compared before and after treatment. Highly radioresistant cells were the most sensitive to 2-DG, whereas intermediate radioresistant cells were sensitive to 2-DG plus BSO/AUR. In response to 2-DG/BSO/AUR treatment, we observed increased levels of intracellular oxidized glutathione, redox-sensitive dye oxidation, and decreased glucose utilization via multiple metabolic pathways including the tricarboxylic acid cycle. 2-DG/BSO/AUR treatment delayed the growth of tumors composed of intermediate radioresistant cells and effectively radiosensitized these tumors at clinically relevant radiation doses both in vitro and in vivo. Overall, our results support inhibition of glycolysis and intracellular redox metabolism as an effective alternative drug strategy for the treatment of highly glycolytic and radioresistant cervical cancers.

Washington University, Departments of Chemistry, Genetics, and Medicine. Saint Louis, Missouri 63110 USA