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
机构:[1]Kunming Med Univ, Biomed Engn Res Ctr, Kunming, Yunnan, Peoples R China;[2]Kunming Med Univ, Affiliated Hosp 1, Dept Urol, Kunming, Peoples R China;昆明医科大学附属第一医院[3]Chinese Univ Hong Kong, Inst Future Cities, Hong Kong, Hong Kong, Peoples R China;[4]Chinese Univ Hong Kong, Dept Comp Sci & Engn, Hong Kong, Hong Kong, Peoples R China;[5]Xuzhou Med Coll, Canc Biotherapy Inst, Xuzhou, Jiangsu Prov, Peoples R China;[6]Yunnan Univ, TCM, Sch Basic Med Sci, Dept Pathophysiol, Kunming, Peoples R China;[7]Kunming Med Univ, Affiliated Hosp 3, Dept Med Oncol 2, Kunming, Peoples R China;[8]Kunming Med Univ, Affiliated Hosp 3, Dept Cadre Med Branch, Kunming, Peoples R China;[9]Chinese Univ Hong Kong, Sch Biomed Sci, Hong Kong, Hong Kong, Peoples R China;[10]Shenzhen Univ, Sch Med, Shenzhen Key Lab Translat Med Tumor, Shenzhen, Peoples R China
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 anti-proliferative 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-alpha, 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.
基金:
Hsiang-fu Kung academician workstation of Kunming Medical University [NSFC 81272549]; Key Lab project of Shenzhen of the P.R. China [ZDSY 20130329101130496]; Scientific Research Fund project of Department of Education of Yunnan Province [2015J051]; Chinese University of Hong KongChinese University of Hong Kong; Research Grants Council of Hong Kong SARHong Kong Research Grants Council [414413, 772910, 470911]
第一作者机构:[1]Kunming Med Univ, Biomed Engn Res Ctr, Kunming, Yunnan, Peoples R China;[2]Kunming Med Univ, Affiliated Hosp 1, Dept Urol, Kunming, Peoples R China;
通讯作者:
通讯机构:[4]Chinese Univ Hong Kong, Dept Comp Sci & Engn, Hong Kong, Hong Kong, Peoples R China;[10]Shenzhen Univ, Sch Med, Shenzhen Key Lab Translat Med Tumor, Shenzhen, Peoples R China
推荐引用方式(GB/T 7714):
Ke Kunbin,Li Hongjian,Yao Hong,et al.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[J].CHEMICAL BIOLOGY & DRUG DESIGN.2017,89(4):505-513.doi:10.1111/cbdd.12872.
APA:
Ke, Kunbin,Li, Hongjian,Yao, Hong,Shi, Xi-Nan,Dong, Chao...&Lin, Marie Chia-mi.(2017).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.CHEMICAL BIOLOGY & DRUG DESIGN,89,(4)
MLA:
Ke, Kunbin,et al."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".CHEMICAL BIOLOGY & DRUG DESIGN 89..4(2017):505-513