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

• 作者: Feiyun Wang Guoqiang Lin Jiange Zhang Jiazhen Xu Liuqing Yang Lixian Jiang Pei Zhang Pengwei Luan Qianfei Cui Ruixiang Li Xinyue Ding Xiyan Yang Yuying Zhu
• 来源期刊: 药学学报（英文版）
• 年，卷（期）: 2020,（8）
• 所属期刊栏目: Original articles
• 页码范围: 1414-1425
• 页数: 12页
• 语种: 英文

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 antiangiogenesis 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.