Niclosamide and its analogs are potent inhibitors of Wnt/β-catenin, mTOR and STAT3 signaling in ovarian cancer.
Niclosamide and its analogs are potent inhibitors of Wnt/β-catenin, mTOR and STAT3 signaling in ovarian cancer.
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DOI：
10.18632/oncotarget.13466
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发表时间：
2016-12-27
期刊：
影响因子：
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通讯作者：
Buchsbaum DJ
中科院分区：
文献类型：
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作者：
Arend RC;Londoño-Joshi AI;Gangrade A;Katre AA;Kurpad C;Li Y;Samant RS;Li PK;Landen CN;Yang ES;Hidalgo B;Alvarez RD;Straughn JM;Forero A;Buchsbaum DJ
上皮性卵巢癌（EOC）是全球妇科癌症死亡率的主要原因。基于铂的治疗是标准的一线治疗，虽然大多数患者最初有反应，但通常会出现对化疗的耐药性。在化学抗性细胞中经常上调并且在癌症干细胞（CSC）的维持中重要的主要信号传导途径包括Wnt/β-连环蛋白、mTOR和STAT 3。我们研究的主要目的是研究用抑制这三种途径的靶向药物治疗卵巢癌。在这里，我们证明，氯硝柳胺，水杨酰胺衍生物，和两个合成制造的氯硝柳胺类似物（类似物11和32）引起显着抑制增殖的两个化疗耐药卵巢癌细胞系（A2780 cp 20和SKOV 3 Trip 2），从卵巢癌患者的腹水中分离的肿瘤球，和细胞从化疗耐药患者来源的异种移植物（PDX）。这项工作表明，所有三种药物均显著降低了Wnt/β-catenin、mTOR和STAT 3通路中蛋白质的表达，并优先靶向表达卵巢CSC表面蛋白CD 133的细胞。它还说明了药物再利用的化学耐药EOC的潜力，并可以作为一个基础的途径为导向的体内研究。
Epithelial ovarian cancer (EOC) is the leading cause of gynecologic cancer mortality worldwide. Platinum-based therapy is the standard first line treatment and while most patients initially respond, resistance to chemotherapy usually arises. Major signaling pathways frequently upregulated in chemoresistant cells and important in the maintenance of cancer stem cells (CSCs) include Wnt/β-catenin, mTOR, and STAT3. The major objective of our study was to investigate the treatment of ovarian cancer with targeted agents that inhibit these three pathways. Here we demonstrate that niclosamide, a salicylamide derivative, and two synthetically manufactured niclosamide analogs (analog 11 and 32) caused significant inhibition of proliferation of two chemoresistant ovarian cancer cell lines (A2780cp20 and SKOV3Trip2), tumorspheres isolated from the ascites of EOC patients, and cells from a chemoresistant patient-derived xenograft (PDX). This work shows that all three agents significantly decreased the expression of proteins in the Wnt/β-catenin, mTOR and STAT3 pathways and preferentially targeted cells that expressed the ovarian CSC surface protein CD133. It also illustrates the potential of drug repurposing for chemoresistant EOC and can serve as a basis for pathway-oriented in vivo studies.