Posaconazole, a Second-Generation Triazole Antifungal Drug, Inhibits the Hedgehog Signaling Pathway and Progression of Basal Cell Carcinoma.
Posaconazole, a Second-Generation Triazole Antifungal Drug, Inhibits the Hedgehog Signaling Pathway and Progression of Basal Cell Carcinoma.
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DOI：
10.1158/1535-7163.mct-15-0729-t
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发表时间：
2016-05
影响因子：
5.7
通讯作者：
Kim J
中科院分区：
文献类型：
--
作者：
Chen B;Trang V;Lee A;Williams NS;Wilson AN;Epstein EH Jr;Tang JY;Kim J
Hedgehog(HH)信号通路的失控与多种恶性肿瘤的发生有关，包括基底细胞癌(BCC)。目前可用的或正在进行临床研究的HH途径的抑制剂都能结合和拮抗Smoothens(SMO)，引起显著的但短暂的临床反应。肿瘤再生长和治疗失败归因于这些小分子SMO拮抗剂结合部位的突变。抗真菌药物伊曲康唑被证明是一种有效的SMO拮抗剂，其作用机制与现有的SMO抑制剂不同。然而，伊曲康唑由于其众多的药物-药物相互作用，代表了一种次优的治疗选择。在这里，我们表明泊沙康唑是第二代三唑类抗真菌药物，具有最小的药物相互作用和良好的副作用，也是在SMO水平上发挥作用的HH途径的有效抑制剂。我们证明泊沙康唑抑制HH途径的机制不同于环多巴胺和其他环多巴胺竞争性SMO拮抗剂，但与伊曲康唑相似，具有强大的抗耐药SMO突变体的活性，并在体内抑制HH依赖的基底细胞癌的生长。我们的结果表明，泊沙康唑单独或与其他HH途径拮抗剂联合使用，可以很容易地在临床研究中用于治疗HH依赖的癌症。
Deregulation of Hedgehog (Hh) pathway signaling has been associated with the pathogenesis of various malignancies, including basal cell carcinomas (BCC). Inhibitors of the Hh pathway currently available or under clinical investigation all bind and antagonize Smoothened (SMO), inducing a marked but transient clinical response. Tumor regrowth and therapy failure were attributed to mutations in the binding site of these small molecule SMO antagonists. The anti-fungal itraconazole was demonstrated to be a potent SMO antagonist with a distinct mechanism of action from that of current SMO inhibitors. However, itraconazole represents a suboptimal therapeutic option due to its numerous drug-drug interactions. Here we show that posaconazole, a second generation triazole anti-fungal with minimal drug-drug interactions and a favorable side effect profile, is also a potent inhibitor of the Hh pathway that functions at the level of SMO. We demonstrate that posaconazole inhibits the Hh pathway by a mechanism distinct from that of cyclopamine and other cyclopamine-competitive SMO antagonists but similar to itraconazole, has robust activity against drug-resistant SMO mutants and inhibits the growth of Hh-dependent basal cell carcinoma in vivo. Our results suggest that posaconazole, alone or in combination with other Hh pathway antagonists, may be readily tested in clinical studies for the treatment of Hh-dependent cancers.