Discovery of the Anti-Angiogenesis Effect of Eltrombopag in Breast Cancer Through Targeting of HuR Protein
| Autor: | Qianfei Cui, Jiazhen Xu, Pei Zhang, Xiyan Yang, Yuying Zhu, Pengwei Luan, Lixian Jiang, Xinyue Ding, Liuqing Yang, Jiange Zhang, Feiyun Wang, Guoqiang Lin, Ruixiang Li |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Oncology
Angiogenesis EMSA electrophoretic mobility shift assay Cell Traditional Chinese medicine HTS high-throughput screening Anti-tumor chemistry.chemical_compound 0302 clinical medicine HUVEC human umbilical vein endothelial cell ELISA enzyme linked immune sorbent assay General Pharmacology Toxicology and Pharmaceutics ARE AU-rich element ELB eltrombopag media_common 0303 health sciences qRT-PCR quantitative real-time PCR RIP RNA immunoprecipitation medicine.anatomical_structure Drug development 030220 oncology & carcinogenesis HuR Original Article FP fluorescence polarization IHC immunohistochemistry Drug medicine.medical_specialty media_common.quotation_subject Eltrombopag SPR surface plasmon resonance mRNAs stability 03 medical and health sciences Breast cancer In vivo Internal medicine medicine Electrophoretic mobility shift assay 030304 developmental biology Matrigel HuR human antigen R Cell growth business.industry lcsh:RM1-950 medicine.disease In vitro lcsh:Therapeutics. Pharmacology chemistry Cancer research business |
| Zdroj: | Acta Pharmaceutica Sinica B, Vol 10, Iss 8, Pp 1414-1425 (2020) Acta Pharmaceutica Sinica. B |
| ISSN: | 1556-5068 |
| DOI: | 10.2139/ssrn.3424182 |
| Popis: | 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. Graphical abstract This study elucidated the anti-tumor effect and new mechanism of the clinical drug eltrombopag, where eltrombopag exhibited anti-tumor angiogenesis effect through targeting HuR protein in cancer cells and macrophages. With these data, we emphasize the efficiency of HuR inhibitor for tumor angiogenesis inhibition.Image 1 |
| Databáze: | OpenAIRE |
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