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
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
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杀螨剂氟啶脲作为 FGFR3 潜在抑制剂和膀胱癌候选抗癌药物的计算机预测和体内外验证
DOI：
10.1111/cbdd.12872
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发表时间：
2017-04-01
影响因子：
3
通讯作者：
Lin, Marie Chia-mi
中科院分区：
文献类型：
--
作者：
Ke, Kunbin;Li, Hongjian;Lin, Marie Chia-mi
膀胱癌（BC）是全球第九大常见癌症病因。由于肿瘤复发和耐药，手术切除和常规化疗、放疗最终会失败。因此，迫切需要开发新的治疗方法。成纤维细胞生长因子受体3 （FGFR3）是治疗BC的重要靶点。在这项研究中，我们利用免费和开源的蛋白质配体对接软件idock，通过重新定位策略，从全球3167种已批准的小分子药物中前瞻性地鉴定出FGFR3的潜在抑制剂。购买六种高分化合物并进行体外测试。其中，杀螨药氟唑龙对人BC细胞系RT112和RT4的抑制增殖作用最高。我们进一步证明，氟唑龙处理显著增加凋亡细胞的百分比，降低FGFR3及其下游蛋白frs2 - α、AKT和ERK的磷酸化水平。我们还研究了氟唑龙对RT112细胞皮下移植BALB/C裸鼠的体内抗癌作用。我们的研究结果表明，口服氟唑龙（80 mg/kg）可显著抑制肿瘤生长。这些结果首次表明氟唑龙是FGFR3的潜在抑制剂和治疗BC的候选抗癌药物。
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.