TY - JOUR
T1 - Radioresistant cervical cancers are sensitive to inhibition of glycolysis and redox metabolism
AU - Rashmi, Ramachandran
AU - Huang, Xiaojing
AU - Floberg, John M.
AU - Elhammali, Adnan E.
AU - McCormick, Michael L.
AU - Patti, Gary J.
AU - Spitz, Douglas R.
AU - Schwarz, Julie K.
N1 - Funding Information:
This work was supported by NIH R01CA181745 (to J.K. Schwarz), Resident Research Seed Grant 531448 from the American Society for Radiation Oncology (to J.M. Floberg), Research Medical Student Grants from the Radiological Society of North America (RSNA) RMS1612 (to X. Huang) and RMS1408 (to A.E. Elhammali), and NIH R01ES022181 and R21CA191097 (to G.J. Patti). The Small Animal Radiation Research Platform was purchased with the assistance of NIH S10 OD020136 (to D. Hallahan). The work at the University of Iowa done by the Radiation and Free Radical Research Core Lab was partially supported by NIH R01 CA182804 and NIH P30 CA086862 (to D.R. Spitz). We would like to thank Michael Zahner and Cedric Mpoy for technical assistance.
Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2018/3/15
Y1 - 2018/3/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85047759127&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-17-2367
DO - 10.1158/0008-5472.CAN-17-2367
M3 - Article
C2 - 29339540
AN - SCOPUS:85047759127
VL - 78
SP - 1392
EP - 1403
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 6
ER -