In silico prediction and in vitro and in vivo validation of acaricide fluazuron as a potential inhibitor of FGFR3 and a candidate anticancer drug for bladder carcinoma
| Autor: | Kwong-Sak Leung, Ying Zhu, Chao Dong, Marie Chia-mi Lin, Man Hon Wong, Kunbin Ke, Ling Li, Hong Yao, Xi-Nan Shi, Xiao-Dong Liu, Hongjian Li, Xu Liu, Hsiang-Fu Kung |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway Drug media_common.quotation_subject Antineoplastic Agents Apoptosis In Vitro Techniques Pharmacology Crystallography X-Ray Biochemistry 03 medical and health sciences 0302 clinical medicine In vivo Cell Line Tumor Drug Discovery Carcinoma medicine Humans Receptor Fibroblast Growth Factor Type 3 Phosphorylation Acaricides media_common business.industry Phenylurea Compounds Organic Chemistry Fibroblast growth factor receptor 3 medicine.disease In vitro Molecular Docking Simulation Drug repositioning 030104 developmental biology Urinary Bladder Neoplasms 030220 oncology & carcinogenesis Molecular Medicine business Signal Transduction |
| Zdroj: | Chemical Biology & Drug Design. 89:505-513 |
| ISSN: | 1747-0277 |
| Popis: | Bladder carcinoma (BC) is the ninth most common cause of cancer worldwide. Surgical resection and conventional chemotherapy and radiotherapy will ultimately fail due to tumor recurrence and resistance. Thus, the development of novel treatment is urgently needed. Fibroblast growth factor receptor 3 (FGFR3) is an important and well-established target for BC treatment. In this study, we utilized the free and open-source protein-ligand docking software idock to prospectively identify potential inhibitors of FGFR3 from 3,167 worldwide approved small-molecule drugs using a repositioning strategy. Six high-scoring compounds were purchased and tested in vitro. Among them, the acaricide drug fluazuron exhibited the highest antiproliferative effect in human BC cell lines RT112 and RT4. We further demonstrated that fluazuron treatment significantly increased the percentage of apoptosis cells, and decreased the phosphorylation level of FGFR3 and its downstream proteins FRS2-α, AKT, and ERK. We also investigated the anticancer effect of fluazuron in vivo in BALB/C nude mice subcutaneously xenografted with RT112 cells. Our results showed that oral treatment with fluazuron (80 mg/kg) significantly inhibited tumor growth. These results suggested for the first time that fluazuron is a potential inhibitor of FGFR3 and a candidate anticancer drug for the treatment of BC. |
| Databáze: | OpenAIRE |
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