Radioresistant Cervical Cancers Are Sensitive to Inhibition of Glycolysis and Redox Metabolism.

Abstract

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.Significance: This study suggests a simple metabolic approach to strike at an apparent Achilles' heel in highly glycolytic, radioresistant forms of cervical cancers, possibly with broader applications in cancer therapy. Cancer Res; 78(6); 1392-403. ©2018 AACR.

• Authors: Ramachandran Rashmi, Xiaojing Huang, John M Floberg, Adnan E Elhammali, Michael L McCormick, Gary J Patti, Douglas R Spitz, Julie K Schwarz
• Journal: Cancer research (Cancer Res) Vol. 78 Issue 6 Pg. 1392-1403 (03 15 2018) ISSN: 1538-7445 [Electronic] United States
• PMID: 29339540 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2018 American Association for Cancer Research.

Chemical References

• Reactive Oxygen Species
• Lactic Acid
• Auranofin
• Buthionine Sulfoximine
• Thioredoxins
• Deoxyglucose
• Glutathione

Topics

• Animals
• Auranofin (pharmacology)
• Buthionine Sulfoximine (pharmacology)
• Cell Death (drug effects)
• Cell Line, Tumor
• Citric Acid Cycle (drug effects)
• Deoxyglucose (pharmacology)
• Female
• Glutathione (metabolism)
• Glycolysis (drug effects)
• Humans
• Lactic Acid (metabolism)
• Mice, Nude
• Oxidation-Reduction
• Radiation Tolerance (drug effects)
• Reactive Oxygen Species (metabolism)
• Thioredoxins (metabolism)
• Uterine Cervical Neoplasms (drug therapy, metabolism, pathology, radiotherapy)
• Xenograft Model Antitumor Assays