Discovery of the anti-angiogenesis effect of eltrombopag in breast cancer through targeting of HuR protein

被引：30

作者：

Zhu, Yuying ^{[1
]}

Yang, Liuqing ^{[1
]}

Xu, Jiazhen ^{[1
]}

Yang, Xiyan ^{[2
]}

Luan, Pengwei ^{[2
]}

Cui, Qianfei ^{[2
]}

Zhang, Pei ^{[1
]}

Wang, Feiyun ^{[1
]}

Li, Ruixiang ^{[1
]}

Ding, Xinyue ^{[1
]}

Jiang, Lixian ^{[1
]}

Lin, Guoqiang ^{[1
]}

Zhang, Jiange ^{[1
]}

机构：

[1] Shanghai Univ Tradit Chinese Med, Res Ctr Chiral Drugs, Innovat Res Inst Tradit Chinese Med IRI, Shanghai 201203, Peoples R China

[2] Zhengzhou Univ, Sch Pharmaceut Sci, Inst Drug Discovery & Dev, Zhengzhou 450001, Peoples R China

来源：

ACTA PHARMACEUTICA SINICA B | 2020年 / 10卷 / 08期

基金：

中国国家自然科学基金;

关键词：

HuR; Eltrombopag; Anti-tumor; Angiogenesis; mRNAs stability; POSTTRANSCRIPTIONAL REGULATION; BINDING; EXPRESSION; PROLIFERATION; CELLS; THROMBOCYTOPENIA; IDENTIFICATION; INTERFERES; INHIBITORS; LEUKEMIA;

D O I：

10.1016/j.apsb.2020.02.007

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

HuR (human antigen R), an mRNA-binding protein responsible for poor prognosis in nearly all kinds of malignancies, is a potential anti-tumor target for drug development. While screening HuR inhibitors with a fluorescence polarization (FP) based high-throughput screening (HTS) system, the clinically used drug eltrombopag was identified. Activity of eltrombopag on molecular level was verified with FP, electrophoretic mobility shift assay (EMSA), simulation docking and surface plasmon resonance (SPR). Further, we showed that eltrombopag inhibited in vitro cell proliferation of multiple cancer cell lines and macrophages, and the in vivo anti-tumor activity was also demonstrated in a 4T1 tumor-bearing mouse model. The in vivo data showed that eltrombopag was efficient in reducing microvessels in tumor tissues. We then confirmed the HuR-dependent anti-angiogenesis effect of eltrombopag in 4T1 cells and RAW264.7 macrophages with qRT-PCR, HuR-overexpression and HuR-silencing assays, RNA stability assays, RNA immunoprecipitation and luciferase assays. Finally, we analyzed the in vitro anti- angiogenesis effect of eltrombopag on human umbilical vein endothelial cells (HUVECs) mediated by macrophages with cell scratch assay and in vitro Matrigel angiogenesis assay. With these data, we revealed the HuR-dependent anti-angiogenesis effect of eltrombopag in breast tumor, suggesting that the existing drug eltrombopag may be used as an anti-cancer drug. (C) 2020 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.

引用

页码：1414 / 1425

页数：12

共 49 条

[1] Posttranscriptional regulation of cancer traits by HuR [J].