Journal article
Radioresistant Cervical Cancers Are Sensitive to Inhibition of Glycolysis and Redox Metabolism
Cancer research (Chicago, Ill.), Vol.78(6), pp.1392-1403
03/15/2018
DOI: 10.1158/0008-5472.CAN-17-2367
PMCID: PMC5856626
PMID: 29339540
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
and
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.
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.
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Details
- Title: Subtitle
- Radioresistant Cervical Cancers Are Sensitive to Inhibition of Glycolysis and Redox Metabolism
- Creators
- Ramachandran Rashmi - Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MissouriXiaojing Huang - Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MissouriJohn M Floberg - Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MissouriAdnan E Elhammali - Department of Radiation Oncology, MD Anderson Cancer Center, Houston, TexasMichael L McCormick - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IowaGary J Patti - Departments of Chemistry and Medicine, Washington University, St. Louis, MissouriDouglas R Spitz - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IowaJulie K Schwarz - Department of Cell Biology and Physiology, Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri
- Resource Type
- Journal article
- Publication Details
- Cancer research (Chicago, Ill.), Vol.78(6), pp.1392-1403
- Publisher
- United States
- DOI
- 10.1158/0008-5472.CAN-17-2367
- PMID
- 29339540
- PMCID
- PMC5856626
- ISSN
- 0008-5472
- eISSN
- 1538-7445
- Grant note
- S10 OD020136 / NIH HHS P30 ES005605 / NIEHS NIH HHS R01 CA181745 / NCI NIH HHS R01 CA182804 / NCI NIH HHS R01 ES022181 / NIEHS NIH HHS P30 CA086862 / NCI NIH HHS R21 CA191097 / NCI NIH HHS
- Language
- English
- Date published
- 03/15/2018
- Academic Unit
- Pathology; Radiation Oncology
- Record Identifier
- 9984046907802771
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