Glutaminase Inhibitors Induce Thiol-Mediated Oxidative Stress and Radiosensitization in Treatment-Resistant Cervical Cancers

谷氨酰胺 丁硫胺 谷胱甘肽 谷氨酰胺酶 癌症研究 PI3K/AKT/mTOR通路 氧化应激 细胞凋亡 谷胱甘肽还原酶 谷氨酰胺分解 体内 化学 活性氧 药理学 癌症 癌细胞 抗氧化剂 细胞毒性 程序性细胞死亡 活力测定 DNA损伤 顺铂 细胞培养 细胞生长 生物 生物化学 谷胱甘肽过氧化物酶 氨基酸 生物技术
作者
Ramachandran Rashmi,Kay Jayachandran,Jin Z. Zhang,Vishnu Menon,Naoshad Muhammad,Michael C. Zahner,Fiona Ruiz,Kevin Cho,Yu-Sa Wang,Xiaojing Huang,Yi Huang,Michael L. McCormick,Buck E. Rogers,Douglas R. Spitz,Gary J. Patti,Perry W. Grigsby
出处
期刊:Molecular Cancer Therapeutics [American Association for Cancer Research]
卷期号:19 (12): 2465-2475 被引量:18
标识
DOI:10.1158/1535-7163.mct-20-0271
摘要

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 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.
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