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Chem Biol Drug Des. 2017 Apr;89(4):505-513. doi: 10.1111/cbdd.12872. Epub 2016 Nov 2.

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.

Ke K1,2, Li H3,4, Yao H5, Shi XN1,6, Dong C1,7, Zhu Y1,8, Liu X1, Li L1, Leung KS4, Wong MH4, Liu XD2, Kung HF1,9, Lin MC10.

Author information

1
Biomedical Engineering Research Center, Kunming Medical University, Kunming, Yunnan, China.
2
Department of Urology, The 1st Affiliated Hospital of Kunming Medical University, Kunming, China.
3
Institute of Future Cities, Chinese University of Hong Kong, Hong Kong, China.
4
Department of Computer Science and Engineering, Chinese University of Hong Kong, Hong Kong, China.
5
The Cancer Biotherapy Institute of Jiangsu Province, Xuzhou Medical College, Xuzhou, China.
6
Department of Pathophysiology, School of Basic Medical Sciences, Yunnan University of TCM, Kunming, China.
7
Department of the Second Medical Oncology, The 3rd Affiliated Hospital of Kunming Medical University, Yunnan Tumor Hospital, Kunming, China.
8
Department of Cadre Medical Branch, The 3rd Affiliated Hospital of Kunming Medical University, Kunming, China.
9
School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong, China.
10
Shenzhen Key Lab of Translational Medicine of Tumor, School of Medicine, Shenzhen University, Shenzhen, China.

Abstract

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.

KEYWORDS:

FGFR3 inhibition; Fluazuron; bladder carcinoma; cancer therapy; drug repurposing

PMID:
27664399
DOI:
10.1111/cbdd.12872
[Indexed for MEDLINE]

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