Redeployment-based drug screening identifies the anti-helminthic niclosamide as anti-myeloma therapy that also reduces free light chain production.
Redeployment-based drug screening identifies the anti-helminthic niclosamide as anti-myeloma therapy that also reduces free light chain production.
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DOI：
10.1038/bcj.2011.38
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发表时间：
2011-10
影响因子：
12.8
通讯作者：
Drayson, M. T.
中科院分区：
文献类型：
--
作者：
Khanim, F. L.;Merrick, B. A. M. E.;Giles, H. V.;Jankute, M.;Jackson, J. B.;Giles, L. J.;Birtwistle, J.;Bunce, C. M.;Drayson, M. T.
尽管最近的治疗取得了进展，但多发性骨髓瘤 (MM) 仍然无法治愈，需要新的疗法，特别是对于老年和复发/难治性患者的治疗。我们筛选了 100 种非专利许可口服药物的抗骨髓瘤活性，并鉴定出氯硝柳胺（一种抗蠕虫药）。氯硝柳胺在临床可达到的无毒浓度下，杀死 MM 细胞系和原代 MM 细胞的效率与标准化疗和现有抗骨髓瘤药物单独或组合的效果相同或更好，对正常供体细胞影响很小。细胞死亡与细胞凋亡和自噬标志物相关。重要的是，氯硝柳胺迅速减少 MM 细胞系和原代 MM 的游离轻链 (FLC) 产生。 FLC 是 MM 患者肾功能损害的主要原因，轻链淀粉样蛋白和 FLC 的减少与组织损伤的逆转相关。我们的数据表明，氯硝柳胺的抗MM活性是通过线粒体介导的，伴随着线粒体膜电位的快速丧失、氧化磷酸化的解偶联和线粒体超氧化物的产生。 Niclosamide 还调节 MM 细胞中的核因子-κB 和 STAT3 通路。总之，我们的数据表明，使用氯硝柳胺可以选择性靶向 MM 细胞，同时减少 FLC 分泌。重要的是，氯硝柳胺在这些浓度下广泛使用且毒性最小。
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.
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影响因子：
3.7
作者：
Balgi AD;Fonseca BD;Donohue E;Tsang TC;Lajoie P;Proud CG;Nabi IR;Roberge M
通讯作者：
Roberge M
影响因子：
45.3
作者：
Fermand, J;Katsahian, S;Ravaud, P
通讯作者：
Ravaud, P
影响因子：
3.5
作者：
DiMasi, JA;Hansen, RW;Grabowski, HG
通讯作者：
Grabowski, HG
影响因子：
158.5
作者：
Harousseau, Jean-Luc;Moreau, Philippe
通讯作者：
Moreau, Philippe
影响因子：
3.4
作者：
Gertz, MA;Lacy, MQ;Kyle, RA
通讯作者：
Kyle, RA