Radio-resistant Cervical Cancers Are Sensitive to Inhibition of Glycolysis and Redox Metabolism

Highly glycolytic cervical cancers largely resist treatment by cisplatin and co-administered 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-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 (ROS) were compared before and after treatment. Highly radio-resistant cells were the most sensitive to 2-DG, whereas intermediate radio-resistant cells were sensitive to 2-DG plus BSO/AUR. In response to 2-DG/BSO/AUR treatment, we observed increased levels of intracellular oxidized glutatione, redox-sensitive dye oxidation and decreased glucose utilization via multiple metabolic pathways including the TCA cycle. 2-DG/BSO/AUR treatment delayed the growth of tumors composed of intermediate radio-resistant cells and effectively radio-sensitized 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 radio-resistant cervical cancers.

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