谷氨酰胺分解
谷氨酰胺
癌细胞
化学
活性氧
生物化学
DNA损伤
癌症研究
癌症
氨基酸
生物
DNA
遗传学
作者
Hui Jian,Yun Zhang,Junyue Wang,Zhenxiang Chen,Tingyi Wen
出处
期刊:Nanoscale
[The Royal Society of Chemistry]
日期:2022-01-01
卷期号:14 (24): 8727-8743
被引量:8
摘要
The reprogrammed amino acid metabolism maintains the powerful antioxidant defense and DNA damage repair capacity of cancer cells, which could promote their escape from reactive oxygen species (ROS)-induced damage and inevitably diminish the efficacy of ROS-based therapies. Herein, we propose a strategy to enhance the effect of chemodynamic therapy (CDT) via glutaminolysis-targeted inhibition for cancer cells dependent on abnormal glutamine metabolism. To screen optimum drugs targeting glutamine metabolism, transcriptomic analysis is performed to identify predictive biomarkers. Eventually, telaglenastat (CB-839) is used to block mitochondrial glutaminase 1 (GLS 1) in basal-like breast cancer and loaded into the developed iron-doped zeolitic imidazolate frameworks (ZIF(Fe) NPs) to form ZIF(Fe)&CB nanoparticles, which are able to co-deliver Fe2+ and CB-839 into the tumor. CB-839 induced-glutaminolysis inhibition not only reduces intracellular antioxidants (glutathione, taurine) to amplify Fe2+-induced oxidative stress, but also decreases nucleotide pools (e.g., adenosine, dihydroorotate) to incur the deficiency of building blocks for DNA damage repair, thereby promoting the cell-killing effect of CDT. In vivo assessments further confirm the enhanced anticancer performance and good biocompatibility of ZIF(Fe)&CB nanoparticles. This study provides a promising strategy for the development and improvement of ROS-based anticancer nanosystems.
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