Apatinib Induces Ferroptosis of Glioma Cells through Modulation of the VEGFR2/Nrf2 Pathway

被引:21
|
作者
Xia, Liang [1 ,2 ]
Gong, Mingjie [3 ]
Zou, Yangfan [1 ]
Wang, Zeng [4 ]
Wu, Bin [1 ]
Zhang, Shuyuan [1 ]
Li, Liwen [1 ]
Jin, Kai [1 ]
Sun, Caixing [1 ,2 ]
机构
[1] Chinese Acad Sci, Dept Neurosurg, Univ Chinese Acad Sci, Canc Hosp,Zhejiang Canc Hosp,Inst Basic Med & Can, Hangzhou 310022, Peoples R China
[2] Translat Res Zhejiang Prov, Key Lab Head & Neck Canc, Hangzhou 310022, Peoples R China
[3] Xuzhou Med Univ, Changshu 2 Peoples Hosp, Dept Neurosurg, Affiliated Changshu Hosp, Changshu 215500, Peoples R China
[4] Chinese Acad Sci, Univ Chinese Acad Sci, Zhejiang Canc Hosp, Inst Basic Med & Canc,Canc Hosp,Dept Pharm, Hangzhou 310022, Peoples R China
基金
中国国家自然科学基金;
关键词
D O I
10.1155/2022/9925919
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Background. Glioma is a common tumor that originated from the brain, and molecular targeted therapy is one of the important treatment modalities of glioma. Apatinib is a small-molecule tyrosine kinase inhibitor, which is widely used for the treatment of glioma. However, the underlying molecular mechanism has remained elusive. Recently, emerging evidence has proved the remarkable anticancer effects of ferroptosis. In this study, a new ferroptosis-related mechanism of apatinib inhibiting proliferation of glioma cells was investigated, which facilitated further study on inhibitory effects of apatinib on cancer cells. Methods. Human glioma U251 and U87 cell lines and normal astrocytes were treated with apatinib. Ferroptosis, cell cycle, apoptosis, and proliferation were determined. A nude mouse xenograft model was constructed, and tumor growth rate was detected. Tumor tissues were collected to estimate ferroptosis levels and to identify the relevant pathways after treatment with apatinib. Results. Treatment with apatinib could induce loss of cell viability of glioma cells, but not of normal astrocytes, through eliciting ferroptosis in vitro and in vivo. It was also revealed that apatinib triggered ferroptosis of glioma cells via inhibiting the activation of nuclear factor erythroid 2-related factor 2/vascular endothelial growth factor receptor 2 (Nrf2/VEFGR2) pathway. The overexpression of Nrf2 rescued the therapeutic effects of apatinib. Conclusion. Our study proved that treatment with apatinib could restrain proliferation of glioma cells through induction of ferroptosis via inhibiting the activation of VEGFR2/Nrf2/Keap1 pathway. Overexpression of Nrf2 could counteract the induction of ferroptosis by apatinib.
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页数:15
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