The effects of JNJ-26481585, a novel hydroxamate-based histone deacetylase inhibitor, on the development of multiple myeloma in the 5T2MM and 5T33MM murine models
The effects of JNJ-26481585, a novel hydroxamate-based histone deacetylase inhibitor, on the development of multiple myeloma in the 5T2MM and 5T33MM murine models
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DOI：
10.1038/leu.2009.121
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发表时间：
2009-10-01
期刊：
影响因子：
11.4
通讯作者：
Vanderkerken, K.
中科院分区：
文献类型：
--
作者：
Deleu, S.;Lemaire, M.;Vanderkerken, K.
多发性骨髓瘤（MM）是一种b细胞恶性肿瘤，由于骨髓（BM）微环境控制的耐药性发展，通常无法治愈。因此，迫切需要新的治疗策略。在本研究中，我们利用MM的同基因小鼠5TMM模型，评估了新型“第二代”嘧啶-羟肟酸组蛋白去乙酰化酶抑制剂JNJ-26481585的抗MM活性。在体外，JNJ-26481585在低纳摩尔浓度下诱导caspase级联激活和p21上调，导致骨髓瘤细胞凋亡和细胞周期阻滞。在BM内皮细胞中，使用更高浓度的JNJ-26481585可以观察到类似的结果，表明JNJ-26481585对癌细胞的选择性。在预防和治疗方面，JNJ-26481585治疗导致肿瘤负荷几乎完全减少，血管生成显著减少。携带5t2mm的小鼠也出现了mm相关的骨病，其特征是破骨细胞数量增加、溶骨病变的发生和松质骨的减少。用JNJ-264815治疗这些小鼠可显著减少骨病的发生。这些数据表明，JNJ-26481585具有强大的抗mm活性，可以克服体内BM微环境的刺激作用，使其成为一种有前景的新型抗mm药物。白血病（2009）23,1894 -1903；doi: 10.1038 / leu.2009.121;2009年6月4日在线发布
Multiple myeloma (MM) is a B-cell malignancy, which often remains incurable because of the development of drug resistance governed by the bone marrow (BM) microenvironment. Novel treatment strategies are therefore urgently needed. In this study, we evaluated the anti-MM activity of JNJ-26481585, a novel 'second-generation' pyrimidyl-hydroxamic acid-based histone deacetylase inhibitor, using the syngeneic murine 5TMM model of MM. In vitro, JNJ-26481585 induced caspase cascade activation and upregulation of p21, resulting in apoptosis and cell cycle arrest in the myeloma cells at low nanomolar concentrations. Similar results could be observed in BM endothelial cells using higher concentrations, indicating the selectivity of JNJ-26481585 toward cancer cells. In a prophylactic and therapeutic setting, treatment with JNJ-26481585 resulted in an almost complete reduction of the tumor load and a significant decrease in angiogenesis. 5T2MM-bearing mice also developed a MM-related bone disease, characterized by increased osteoclast number, development of osteolytic lesions and a reduction in cancellous bone. Treatment of these mice with JNJ-264815 significantly reduced the development of bone disease. These data suggest that JNJ-26481585 has a potent anti-MM activity that can overcome the stimulatory effect of the BM microenvironment in vivo making this drug a promising new anti-MM agent. Leukemia (2009) 23, 1894 -1903; doi: 10.1038/leu.2009.121; published online 4 June 2009