Progesterone receptor chaperone complex-based high-throughput screening assay: identification of capsaicin as an inhibitor of the Hsp90 machine.
Progesterone receptor chaperone complex-based high-throughput screening assay: identification of capsaicin as an inhibitor of the Hsp90 machine.
复制标题
DOI：
10.1177/1087057114549147
复制
发表时间：
2015-02
影响因子：
--
通讯作者：
Chadli A
中科院分区：
文献类型：
--
作者：
Patwardhan CA;Alfa E;Lu S;Chadli A
已知 Hsp90 及其共伴侣对于癌细胞的存活很重要。不幸的是，作为抗肿瘤药物正在进行临床试验的 Hsp90 N 端抑制剂在临床上的疗效令人失望。因此，迫切需要具有不同作用机制的新型Hsp90机器抑制剂。我们在此报告了一种新型高通量药物筛选 (HTS) 检测平台的开发，该平台可识别 Hsp90 及其共伴侣的小分子抑制剂。该测定以 96 孔板形式定量测量 Hsp90 及其共伴侣重折叠/保护孕酮受体 (PR) 的能力，孕酮受体 (PR) 是 Hsp90 的生理客户。我们筛选了 NIH 临床保藏药物库，确定辣椒素为命中分子。辣椒素是 FDA 批准的局部用于疼痛管理的药物。细胞存活测定表明，辣椒素选择性杀死癌细胞并破坏多种 Hsp90 客户蛋白的稳定性。因此，我们的数据可以解释辣椒素看似多效的作用。
Hsp90 and its co-chaperones are known to be important for cancer cell survival. The N-terminal inhibitors of Hsp90 that are in ongoing clinical trials as anti-tumor agents have unfortunately shown disappointing efficacies in the clinic. Thus, novel inhibitors of the Hsp90 machine with different mechanism of action are urgently needed. We report here the development of a novel high-throughput drug-screening (HTS) assay platform to identify small molecule inhibitors of Hsp90 and its co-chaperones. This assay quantitatively measures the ability of Hsp90 and its co-chaperones to refold/protect the progesterone receptor (PR), a physiological client of Hsp90, in 96-well plate format. We screened the NIH clinical collection drug library and identified capsaicin as a hit molecule. Capsaicin is an FDA-approved drug for topical use in pain management. Cell survival assays showed that capsaicin selectively kills cancer cells and destabilizes several Hsp90 client proteins. Thus, our data may explain the seemingly pleotropic effect of capsaicin.