文章：

基于重新部署的药物筛选确定了抗蠕虫的氯硝柳胺作为抗骨髓瘤治疗，也减少了游离轻链的产生

Redeployment-based drug screening identifies the anti-helminthic niclosamide as anti-myeloma therapy that also reduces free light chain production

原文发布日期：2011-10-21

DOI: 10.1038/bcj.2011.38

类型: Original Article

开放获取: 是

英文摘要：

Despite recent therapeutic advancements, multiple myeloma (MM) remains incurable and new therapies are needed, especially for the treatment of elderly and relapsed/refractory patients. We have screened a panel of 100 off-patent licensed oral drugs for anti-myeloma activity and identified niclosamide, an anti-helminthic. Niclosamide, at clinically achievable non-toxic concentrations, killed MM cell lines and primary MM cells as efficiently as or better than standard chemotherapy and existing anti-myeloma drugs individually or in combinations, with little impact on normal donor cells. Cell death was associated with markers of both apoptosis and autophagy. Importantly, niclosamide rapidly reduced free light chain (FLC) production by MM cell lines and primary MM. FLCs are a major cause of renal impairment in MM patients and light chain amyloid and FLC reduction is associated with reversal of tissue damage. Our data indicate that niclosamides anti-MM activity was mediated through the mitochondria with rapid loss of mitochondrial membrane potential, uncoupling of oxidative phosphorylation and production of mitochondrial superoxide. Niclosamide also modulated the nuclear factor-κB and STAT3 pathways in MM cells. In conclusion, our data indicate that MM cells can be selectively targeted using niclosamide while also reducing FLC secretion. Importantly, niclosamide is widely used at these concentrations with minimal toxicity.

摘要翻译： 

尽管近期治疗手段有所进展，多发性骨髓瘤（MM）仍无法治愈，尤其对于老年及复发/难治性患者，亟需新型疗法。我们筛选了100种已过专利期的口服药物，评估其抗骨髓瘤活性，并鉴定出抗蠕虫药物氯硝柳胺。在临床可达的非毒性浓度下，氯硝柳胺对MM细胞系及原代MM细胞的杀伤效果与标准化疗及现有抗骨髓瘤单药或联合方案相当或更优，且对正常供体细胞影响甚微。细胞死亡伴随凋亡与自噬标志物同时出现。值得注意的是，氯硝柳胺能快速降低MM细胞系及原代MM细胞的游离轻链（FLC）产量。FLC是导致MM患者肾功能损伤的主要原因，轻链淀粉样变性的改善与FLC水平下降及组织损伤逆转密切相关。我们的数据显示，氯硝柳胺通过作用于线粒体发挥抗MM活性：快速降低线粒体膜电位、解偶联氧化磷酸化过程并促进线粒体超氧化物生成。该药物同时调控MM细胞核因子-κB与STAT3信号通路。综上所述，氯硝柳胺能选择性靶向MM细胞并有效抑制FLC分泌，且现有临床应用表明该浓度下药物毒性极低。

原文链接：

Redeployment-based drug screening identifies the anti-helminthic niclosamide as anti-myeloma therapy that also reduces free light chain production