Effect of niclosamide on basal-like breast cancers.
Effect of niclosamide on basal-like breast cancers.
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DOI：
10.1158/1535-7163.mct-13-0555
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发表时间：
2014-04
影响因子：
5.7
通讯作者：
Buchsbaum DJ
中科院分区：
文献类型：
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作者：
Londoño-Joshi AI;Arend RC;Aristizabal L;Lu W;Samant RS;Metge BJ;Hidalgo B;Grizzle WE;Conner M;Forero-Torres A;Lobuglio AF;Li Y;Buchsbaum DJ
基底细胞样乳腺癌（BLBC）分化差，表现出侵袭性临床行为。这些肿瘤变得对细胞毒性剂具有抗性，并且肿瘤复发归因于癌症干细胞（CSC）的存在。参与CSC调节的途径之一是Wnt/β-连环蛋白信号传导途径。LRP 6是Wnt配体受体，是该途径的关键元件之一，可能是一个很好的治疗靶点。已显示氯硝柳胺通过引起LRP 6降解来抑制Wnt/β-连环蛋白信号传导途径。TRA-8是一种特异于TRAIL死亡受体5的单克隆抗体，对BLBC细胞系及其CSC富集群体具有细胞毒性。本研究的目的是检查氯硝柳胺是否对BLBC，特别是CSC群体具有细胞毒性，以及是否与TRA-8组合可以产生增加的细胞毒性。乙醛脱氢酶（ALDH）是CSC的已知标志物。通过流式细胞术检测BLBC细胞的ALDH表达，我们能够分离出具有高ALDH表达的非粘附细胞群。氯硝柳胺对这些非贴壁ALDH表达细胞以及来自四种BLBC细胞系2LMP、SUM 159、HCC 1187和HCC 1143的贴壁细胞显示出细胞毒性。氯硝柳胺产生降低水平的LRP 6和β-连环蛋白，其是下游Wnt/β-连环蛋白信号传导蛋白。TRA-8和氯硝柳胺的组合产生累加的细胞毒性和Wnt/β-连环蛋白活性的降低。氯硝柳胺与TRA-8组合抑制2LMP原位肿瘤异种移植物的生长。这些结果表明，氯硝柳胺或该药剂的同类物可用于治疗BLBC。
Basal-like breast cancers (BLBCs) are poorly differentiated and display aggressive clinical behavior. These tumors become resistant to cytotoxic agents and tumor relapse has been attributed to the presence of cancer stem cells (CSCs). One of the pathways involved in CSC regulation is the Wnt/β-catenin signaling pathway. LRP6, a Wnt ligand receptor, is one of the critical elements of this pathway and could potentially be an excellent therapeutic target. Niclosamide has been shown to inhibit the Wnt/β-catenin signaling pathway by causing degradation of LRP6. TRA-8, a monoclonal antibody specific to TRAIL death receptor 5, is cytotoxic to BLBC cell lines and their CSC enriched populations. The goal of this study was to examine whether niclosamide is cytotoxic to BLBCs, specifically the CSC population, and if in combination with TRA-8 could produce increased cytotoxicity. Aldehyde dehydrogenase (ALDH) is a known marker of CSCs. By testing BLBC cells for ALDH expression by flow cytometry, we were able to isolate a non-adherent population of cells that have high ALDH expression. Niclosamide showed cytotoxicity against these non-adherent ALDH expressing cells in addition to adherent cells from four BLBC cell lines: 2LMP, SUM159, HCC1187 and HCC1143. Niclosamide produced reduced levels of LRP6 and β-catenin, which is a downstream Wnt/β-catenin signaling protein. The combination of TRA-8 and niclosamide produced additive cytotoxicity and a reduction in Wnt/β-catenin activity. Niclosamide in combination with TRA-8 suppressed growth of 2LMP orthotopic tumor xenografts. These results suggest that niclosamide or congeners of this agent may be useful for the treatment of BLBC.