Drug Repurposing of the Anthelmintic Niclosamide to Treat Multidrug-Resistant Leukemia.
Drug Repurposing of the Anthelmintic Niclosamide to Treat Multidrug-Resistant Leukemia.
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DOI：
10.3389/fphar.2017.00110
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发表时间：
2017
影响因子：
5.6
通讯作者：
Efferth T
中科院分区：
文献类型：
--
作者：
Hamdoun S;Jung P;Efferth T
多重耐药性是导致抗癌化疗失败的一个主要问题，需要开发新药。现有药物的重新利用是解决这一问题的一种有前途的方法。此类药物的一个例子是氯硝柳胺，一种已知的驱虫药，目前已知其对癌细胞具有细胞毒性和细胞抑制作用。在这项研究中，氯硝柳胺对不同的癌细胞系表现出不同的活性。与实体瘤细胞系 MDA-MB-231、A549 和 HT-29 相比，它对血液癌细胞系 CCRF-CEM、CEM/ADR5000 和 RPMI-8226 具有更好的活性。多重耐药 CEM/ADR5000 细胞与其敏感的对应物 CCRF-CEM 具有相似的敏感性（耐药比：1.24）。此外，氯硝柳胺会导致白血病细胞中活性氧和谷胱甘肽（GSH）水平升高。谷胱甘肽合成酶 (GS) 被预测为氯硝柳胺的靶标。分子对接表明，氯硝柳胺可能与GS的ATP结合位点结合，结合能为-9.40 kcal/mol。使用微量热泳法，测量氯硝柳胺和重组人 GS 之间的结合亲和力（结合常数：5.64 μM）。对 60 个细胞系的 NCI 微阵列数据库进行的 COMPARE 分析表明，包括参与脂质代谢的基因在内的多个基因与细胞对氯硝柳胺的反应相关。层次聚类分析显示敏感细胞系和耐药细胞系之间存在显着差异的五个主要分支（p = 8.66 × 105）。正如启动子结合基序分析预测的那样，氯硝柳胺显着降低了活化 T 细胞核因子 (NFAT) 的活性。总之，与实体瘤相比，氯硝柳胺对血液恶性肿瘤更具活性。该药物对多重耐药 CEM/ADR5000 白血病细胞特别有效。抑制 GSH 合成和 NFAT 信号传导被确定为氯硝柳胺抗癌活性的相关机制。基因表达谱预测癌细胞对氯硝柳胺的敏感性或耐药性。
Multidrug resistance, a major problem that leads to failure of anticancer chemotherapy, requires the development of new drugs. Repurposing of established drugs is a promising approach for overcoming this problem. An example of such drugs is niclosamide, a known anthelmintic that is now known to be cytotoxic and cytostatic against cancer cells. In this study, niclosamide showed varying activity against different cancer cell lines. It revealed better activity against hematological cancer cell lines CCRF-CEM, CEM/ADR5000, and RPMI-8226 compared to the solid tumor cell lines MDA-MB-231, A549, and HT-29. The multidrug resistant CEM/ADR5000 cells were similar sensitive as their sensitive counterpart CCRF-CEM (resistance ration: 1.24). Furthermore, niclosamide caused elevations in reactive oxygen species and glutathione (GSH) levels in leukemia cells. GSH synthetase (GS) was predicted as a target of niclosamide. Molecular docking showed that niclosamide probably binds to the ATP-binding site of GS with a binding energy of -9.40 kcal/mol. Using microscale thermophoresis, the binding affinity between niclosamide and recombinant human GS was measured (binding constant: 5.64 μM). COMPARE analyses of the NCI microarray database for 60 cell lines showed that several genes, including those involved in lipid metabolism, correlated with cellular responsiveness to niclosamide. Hierarchical cluster analysis showed five major branches with significant differences between sensitive and resistant cell lines (p = 8.66 × 105). Niclosamide significantly decreased nuclear factor of activated T-cells (NFAT) activity as predicted by promoter binding motif analysis. In conclusion, niclosamide was more active against hematological malignancies compared to solid tumors. The drug was particularly active against the multidrug-resistant CEM/ADR5000 leukemia cells. Inhibition of GSH synthesis and NFAT signaling were identified as relevant mechanisms for the anticancer activity of niclosamide. Gene expression profiling predicted the sensitivity or resistance of cancer cells to niclosamide.