Discovery of the anti-angiogenesis effect of eltrombopag in breast cancer through targeting of HuR protein.
10.1016/j.apsb.2020.02.007
- Author:
Yuying ZHU
1
;
Liuqing YANG
1
;
Jiazhen XU
1
;
Xiyan YANG
2
;
Pengwei LUAN
2
;
Qianfei CUI
2
;
Pei ZHANG
1
;
Feiyun WANG
1
;
Ruixiang LI
1
;
Xinyue DING
1
;
Lixian JIANG
1
;
Guoqiang LIN
1
;
Jiange ZHANG
1
Author Information
1. The Research Center of Chiral Drugs, Innovation Research Institute of Traditional Chinese Medicine (IRI), Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
2. Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China.
- Publication Type:Journal Article
- Keywords:
ARE, AU-rich element;
Angiogenesis;
Anti-tumor;
ELB, eltrombopag;
ELISA, enzyme linked immune sorbent assay;
EMSA, electrophoretic mobility shift assay;
Eltrombopag;
FP, fluorescence polarization;
HTS, high-throughput screening;
HUVEC, human umbilical vein endothelial cell;
HuR;
HuR, human antigen R;
IHC, immunohistochemistry;
RIP, RNA immunoprecipitation;
SPR, surface plasmon resonance;
mRNAs stability;
qRT-PCR, quantitative real-time PCR
- From:
Acta Pharmaceutica Sinica B
2020;10(8):1414-1425
- CountryChina
- Language:English
-
Abstract:
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 cell proliferation of multiple cancer cell lines and macrophages, and the anti-tumor activity was also demonstrated in a 4T1 tumor-bearing mouse model. The 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 anti-angiogenesis effect of eltrombopag on human umbilical vein endothelial cells (HUVECs) mediated by macrophages with cell scratch assay and 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.
