Identification of a new pharmacological activity of the phenylpiperazine derivative naftopidil: tubulin-binding drug
Identification of a new pharmacological activity of the phenylpiperazine derivative naftopidil: tubulin-binding drug
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苯基哌嗪衍生物萘哌地尔新药理活性的鉴定：微管蛋白结合药物
DOI：
10.1007/s12154-014-0122-0
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Ishii K and Sugimura Y
中科院分区：
文献类型：
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作者：
Kim CJ;Tambe Y;Mukaisho K;Sugihara H;Kawauchi A;Inoue H;Ishii K and Sugimura Y
苯基哌嗪衍生物奈福托地尔是一种α1肾上腺素能受体(AR)拮抗剂，已被临床用于治疗良性前列腺增生症。在我们的药物定位研究中，奈福托地尔表现出独特的生长抑制作用。奈福托地尔不仅能抑制癌细胞的细胞周期进程，还能抑制成纤维细胞和血管内皮细胞的周期进程。萘哌地尔抑制细胞周期进程不依赖于细胞内α1-AR的表达。因此，萘哌地尔的抗增殖作用可能与药物的非靶向作用有关。在这项研究中，我们尝试使用磁性纳米棒，甲基丙烯酸铁缩水甘油酯(FG)小球来识别奈托地尔的靶外分子。与萘哌地尔类似，其衍生物TG09-01和TG09-02被引入氨基以固定在FG小球上，对人结肠腺癌细胞HT29的生长具有抑制作用。这两种衍生物都与抑制HT29细胞的细胞周期进程有关。这一观察结果与服用萘哌地尔的结果一致。使用TG09-02固定化FG微球，α-微管蛋白和β-微管蛋白被鉴定为萘托地尔的特异性结合蛋白。微管蛋白聚合实验表明，奈福托地尔直接与微管蛋白结合，抑制微管蛋白的聚合。其他苯基哌嗪衍生物如RS100329、BMY7378和KN-62也能抑制微管蛋白的聚合。这些结果表明，苯基哌嗪类化合物，包括萘哌地尔，可能在不同类型的细胞中具有广谱的细胞毒性。此外，苯基哌嗪类化合物对微管蛋白聚合的抑制活性可能是苯基哌嗪类化合物结构的一个特殊特征。这些发现可以让我们设计和合成新的微管蛋白结合药物，这些药物是从萘哌地尔中衍生出来的先导化合物。
The phenylpiperazine derivative naftopidil is an α1-adrenoceptor (AR) antagonist that has been used clinically to treat benign prostatic hyperplasia. In our drug repositioning research, naftopidil shows the unique growth-inhibitory effects. Naftopidil inhibits cell cycle progression not only in cancer cells, but also in fibroblasts and vascular endothelial cells. Naftopidil-inhibited cell cycle progression is independent of α1-AR expression in cells. Therefore, the antiproliferative effects of naftopidil may be due to the off-target effects of the drug. In this study, we attempted to identify the off-target molecules of naftopidil using the magnetic nanobeads, ferrite glycidyl metharcrylate (FG) beads. Similar to naftopidil, its derivatives TG09-01 and TG09-02, which were introduced with amino groups for immobilizing to FG beads, inhibited cell growth in human HT29 colon adenocarcinoma cells. Both derivatives were associated with inhibition of cell cycle progression in HT29 cells. This observation is consistent with that seen with naftopidil. Using TG09-02-immobilized FG beads, α- and β-tubulins were identified as the specific binding proteins of naftopidil. The tubulin polymerization assay clearly indicated that naftopidil bound directly to tubulin and inhibited the polymerization of tubulin. Other phenylpiperazine derivatives, such as RS100329, BMY7378, and KN-62, also inhibited the polymerization of tubulin. These results suggest that phenylpiperazine derivatives including naftopidil may have broad spectrum of cellular cytotoxicity in various types of cells. In addition, the tubulin polymerization-inhibiting activity of phenylpiperazine derivatives may be a specific feature of the phenylpiperazine-based structure. These findings can allow us to design and synthesize new tubulin-binding drugs derived from naftopidil as a lead compound.