Therapeutic effects of the novel subtype-selective histone deacetylase inhibitor chidamide on myeloma-associated bone disease.
Therapeutic effects of the novel subtype-selective histone deacetylase inhibitor chidamide on myeloma-associated bone disease.
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新型亚型选择性组蛋白脱乙酰酶抑制剂西达本胺对骨髓瘤相关骨病的治疗作用
DOI：
10.3324/haematol.2017.181172
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发表时间：
2018-08
期刊：
影响因子：
10.1
通讯作者：
Cai Z
中科院分区：
文献类型：
--
作者：
He J;Chen Q;Gu H;Chen J;Zhang E;Guo X;Huang X;Yan H;He D;Yang Y;Zhao Y;Wang G;He H;Yi Q;Cai Z
组蛋白脱乙酰酶是血液恶性肿瘤有希望的治疗靶点。在本文的工作中，我们使用不同的模型研究了中国自主生产的新型亚型选择性组蛋白脱乙酰酶抑制剂西达本胺对多发性骨髓瘤及其相关骨疾病的影响。西达本胺对骨髓瘤的细胞毒性是由于其通过增加 caspase 家族蛋白 p21 和 p27 等的水平来诱导细胞凋亡和细胞周期停滞。此外，西达本胺对与骨间充质基质细胞和西达本胺预处理的破骨细胞共培养的骨髓瘤细胞表现出显着的细胞毒性。重要的是，西达本胺通过 p-ERK、p-p38、p-AKT 和 p-JNK 去磷酸化并抑制组织蛋白酶 K、NFATc1 和 c-fos 的表达，在体外抑制破骨细胞分化和吸收。最后，西达本胺不仅通过部分减轻肿瘤负荷来防止播散性小鼠模型中与肿瘤相关的骨丢失，而且还可以在非荷瘤小鼠模型中防止核因子κ-β配体快速受体激活剂（RANKL）诱导的骨丢失。根据我们的结果，西达本胺在体外和体内发挥双重抗骨髓瘤和骨保护作用。这些发现有力地支持了该药物在不久的将来可能在临床上用于治疗多发性骨髓瘤。
Histone deacetylases are promising therapeutic targets in hematological malignancies. In the work herein, we investigated the effect of chidamide, a new subtype-selective histone deacetylase inhibitor that was independently produced in China, on multiple myeloma and its associated bone diseases using different models. The cytotoxicity of chidamide toward myeloma is due to its induction of cell apoptosis and cell cycle arrest by increasing the levels of caspase family proteins p21 and p27, among others. Furthermore, chidamide exhibited significant cytotoxicity against myeloma cells co-cultured with bone mesenchymal stromal cells and chidamide-pretreated osteoclasts. Importantly, chidamide suppressed osteoclast differentiation and resorption in vitro by dephosphorylating p-ERK, p-p38, p-AKT and p-JNK and inhibiting the expression of Cathepsin K, NFATc1 and c-fos. Finally, chidamide not only prevented tumor-associated bone loss in a disseminated murine model by partially decreasing the tumor burden but also prevented rapid receptor activator of nuclear factor κ-β ligand (RANKL)-induced bone loss in a non-tumor-bearing mouse model. Based on our results, chidamide exerted dual anti-myeloma and bone-protective effects in vitro and in vivo. These findings strongly support the potential clinical use of this drug as a treatment for multiple myeloma in the near future.
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影响因子：
3.7
作者：
Garcia-Gomez A;Ocio EM;Crusoe E;Santamaria C;Hernández-Campo P;Blanco JF;Sanchez-Guijo FM;Hernández-Iglesias T;Briñón JG;Fisac-Herrero RM;Lee FY;Pandiella A;San Miguel JF;Garayoa M
通讯作者：
Garayoa M
影响因子：
168.9
作者：
Roellig, Christoph;Knop, Stefan;Bornhaeuser, Martin
通讯作者：
Bornhaeuser, Martin
CS055 (Chidamide/HBI-8000) 是一种新型组蛋白脱乙酰酶抑制剂，可诱导人白血病细胞 G1 期阻滞、ROS 依赖性细胞凋亡和分化
影响因子：
4.1
作者：
Gong, Ke;Xie, Jia;Li, Wenhua
通讯作者：
Li, Wenhua
影响因子：
10.1
作者：
Liang, Pei;Cheng, Suk Hang;Ng, Margaret H. L.
通讯作者：
Ng, Margaret H. L.
影响因子：
82.9
作者：
Ortega-Molina A;Boss IW;Canela A;Pan H;Jiang Y;Zhao C;Jiang M;Hu D;Agirre X;Niesvizky I;Lee JE;Chen HT;Ennishi D;Scott DW;Mottok A;Hother C;Liu S;Cao XJ;Tam W;Shaknovich R;Garcia BA;Gascoyne RD;Ge K;Shilatifard A;Elemento O;Nussenzweig A;Melnick AM;Wendel HG
通讯作者：
Wendel HG