Glutaminase Inhibitors Induce Thiol-Mediated Oxidative Stress and Radiosensitization in Treatment-Resistant Cervical Cancers
| Autor: | Douglas R. Spitz, Vishnu Menon, Kevin Cho, Michael C. Zahner, Yuting Wang, Naoshad Muhammad, Jin Zhang, Ramachandran Rashmi, Julie K. Schwarz, Xiaojing Huang, Buck E. Rogers, Gary J. Patti, Sisi Zhang, Yi Huang, Michael L. McCormick, Kay Jayachandran, Fiona Ruiz |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Radiation-Sensitizing Agents Cancer Research Auranofin Cell Survival Glutamine Uterine Cervical Neoplasms medicine.disease_cause Article Mice Phosphatidylinositol 3-Kinases 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Glutaminase In vivo Cell Line Tumor medicine Animals Humans Sulfhydryl Compounds Enzyme Inhibitors PI3K/AKT/mTOR pathway Glutathione Xenograft Model Antitumor Assays Disease Models Animal Oxidative Stress 030104 developmental biology Oncology chemistry Drug Resistance Neoplasm 030220 oncology & carcinogenesis Cancer research Glutathione disulfide Female Reactive Oxygen Species Glycolysis Oxidative stress medicine.drug |
| Zdroj: | Mol Cancer Ther |
| ISSN: | 1538-8514 1535-7163 |
| Popis: | 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 vitro 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. In vivo 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 in vitro and in vivo. 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. |
| Databáze: | OpenAIRE |
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