Journal article
Glutaminase Inhibitors Induce Thiol-Mediated Oxidative Stress and Radiosensitization in Treatment-Resistant Cervical Cancers
Molecular cancer therapeutics, Vol.19(12), pp.2465-2475
12/2020
DOI: 10.1158/1535-7163.MCT-20-0271
PMCID: PMC8208465
PMID: 33087507
Abstract
The purpose of this study was to determine if radiation (RT)-resistant cervical cancers are dependent upon glutamine metabolism driven by activation of the PI3K pathway and test whether PI3K pathway mutation predicts radiosensitization by inhibition of glutamine metabolism. Cervical cancer cell lines with and without PI3K pathway mutations, including SiHa and SiHa PTEN
cells engineered by CRISPR/Cas9, were used for mechanistic studies performed
in the presence and absence of glutamine starvation and the glutaminase inhibitor, telaglenastat (CB-839). These studies included cell survival, proliferation, quantification of oxidative stress parameters, metabolic tracing with stable isotope-labeled substrates, metabolic rescue, and combination studies with L-buthionine sulfoximine (BSO), auranofin (AUR), and RT.
studies of telaglenastat ± RT were performed using CaSki and SiHa xenografts grown in immune-compromised mice. PI3K-activated cervical cancer cells were selectively sensitive to glutamine deprivation through a mechanism that included thiol-mediated oxidative stress. Telaglenastat treatment decreased total glutathione pools, increased the percent glutathione disulfide, and caused clonogenic cell killing that was reversed by treatment with the thiol antioxidant, N-acetylcysteine. Telaglenastat also sensitized cells to killing by glutathione depletion with BSO, thioredoxin reductase inhibition with AUR, and RT. Glutamine-dependent PI3K-activated cervical cancer xenografts were sensitive to telaglenastat monotherapy, and telaglenastat selectively radiosensitized cervical cancer cells
and
These novel preclinical data support the utility of telaglenastat for glutamine-dependent radioresistant cervical cancers and demonstrate that PI3K pathway mutations may be used as a predictive biomarker for telaglenastat sensitivity.
Details
- Title: Subtitle
- Glutaminase Inhibitors Induce Thiol-Mediated Oxidative Stress and Radiosensitization in Treatment-Resistant Cervical Cancers
- Creators
- Ramachandran Rashmi - Washington University in St. LouisKay Jayachandran - Washington University in St. LouisJin Zhang - Washington University in St. LouisVishnu Menon - Washington University in St. LouisNaoshad Muhammad - Washington University in St. LouisMichael Zahner - Washington University in St. LouisFiona Ruiz - Washington University in St. LouisSisi Zhang - Department of Chemistry, Washington University School of Medicine, St. Louis, MissouriKevin Cho - Washington University in St. LouisYuting Wang - Washington University in St. LouisXiaojing Huang - Memorial Sloan Kettering Cancer CenterYi Huang - Washington University in St. LouisMichael L McCormick - University of IowaBuck E Rogers - Washington University in St. LouisDouglas R Spitz - HoldenGary J Patti - Washington University in St. LouisJulie K Schwarz - Alvin J. Siteman Center, Washington University School of Medicine, St. Louis, Missouri
- Resource Type
- Journal article
- Publication Details
- Molecular cancer therapeutics, Vol.19(12), pp.2465-2475
- DOI
- 10.1158/1535-7163.MCT-20-0271
- PMID
- 33087507
- PMCID
- PMC8208465
- NLM abbreviation
- Mol Cancer Ther
- ISSN
- 1535-7163
- eISSN
- 1538-8514
- Grant note
- R01 CA181745 / NCI NIH HHS P30 ES005605 / NIEHS NIH HHS P01 CA217797 / NCI NIH HHS P30 CA086862 / NCI NIH HHS R35 ES028365 / NIEHS NIH HHS
- Language
- English
- Date published
- 12/2020
- Academic Unit
- Pathology; Radiation Oncology; Fraternal Order of Eagles Diabetes Research Center
- Record Identifier
- 9984312963902771
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