Sertaconazole induced toxicity in HeLa cells through mitotic arrest and inhibition of microtubule assembly
Sertaconazole induced toxicity in HeLa cells through mitotic arrest and inhibition of microtubule assembly
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DOI：
10.1007/s00210-021-02059-5
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发表时间：
2021-02-23
影响因子：
3.6
通讯作者：
Rathinasamy, Krishnan
中科院分区：
文献类型：
--
作者：
Sebastian, Jomon;Rathinasamy, Krishnan
评价了益康唑、咪康唑和舍他康唑（具有咪唑部分的结构相关唑类）的细胞毒性及其与哺乳动物微管蛋白结合的能力。我们的研究结果表明，舍他康唑和益康唑结合羊脑微管蛋白的解离常数分别为9和19 μ M，而咪康唑不结合羊脑微管蛋白。益康唑，咪康唑，和舍他康唑抑制HeLa细胞的增殖与IC 50分别为28，98，和38 μ M，舍他康唑单独诱导有丝分裂阻滞在处理的细胞。由于舍他康唑与羊脑微管蛋白的结合亲和力较高，并在有丝分裂时阻断细胞，我们推测其细胞毒性机制可能涉及抑制微管蛋白，而益康唑在有丝分裂时不阻断细胞，可能具有比微管蛋白更多的靶点。舍他康唑抑制HeLa细胞微管蛋白的聚合和体外组装的羊脑微管蛋白。竞争性微管蛋白结合试验，使用秋水仙碱和计算机模拟研究表明，舍他康唑结合更接近秋水仙碱的网站，并诱导微管蛋白二聚体采取“弯曲”的构象，这是无能的聚合。用舍他康唑处理的A549细胞的RT-PCR分析结果表明凋亡被激活。舍他康唑显著抑制HeLa细胞的迁移，并与长春碱显示出协同抗增殖潜力。总的来说，这些结果表明，已经在临床实践中的舍他康唑可以作为一种局部化疗药物，与其他全身性抗癌药物联合治疗皮肤癌。
Econazole, miconazole, and sertaconazole, the structurally related azoles with imidazole moiety, were evaluated for their cytotoxicity and their ability to bind to mammalian tubulin. Our results indicated that sertaconazole and econazole bound to goat brain tubulin with a dissociation constant of 9 and 19 mu M respectively, while miconazole did not bind to goat brain tubulin. Econazole, miconazole, and sertaconazole inhibited the proliferation of HeLa cells with an IC50 of 28, 98, and 38 mu M respectively with sertaconazole alone inducing a mitotic block in the treated cells. Since sertaconazole bound to goat brain tubulin with higher affinity and blocked the cells at mitosis, we hypothesized that its cytotoxic mechanism might involve inhibition of tubulin and econazole which did not block the cells at mitosis may have additional targets than tubulin. Sertaconazole inhibited the polymerization of tubulin in HeLa cells and the in vitro assembled goat brain tubulin. Competitive tubulin-binding assay using colchicine and computational simulation studies showed that sertaconazole bound closer to the colchicine site and induced the tubulin dimer to adopt a "bent" conformation which is incompetent for the polymerization. Results from RT-PCR analysis of the A549 cells treated with sertaconazole indicated activation of apoptosis. Sertaconazole significantly inhibited the migration of HeLa cells and showed synergistic antiproliferative potential with vinblastine. Collectively, the results suggest that sertaconazole which is already in clinical practice could be useful as a topical chemotherapy agent for the treatment of skin cancers in combination with other systemic anticancer agents.