HDAC inhibitors and decitabine are highly synergistic and associated with unique gene-expression and epigenetic profiles in models of DLBCL
HDAC inhibitors and decitabine are highly synergistic and associated with unique gene-expression and epigenetic profiles in models of DLBCL
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DOI：
10.1182/blood-2011-02-336891
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发表时间：
2011-11-17
期刊：
影响因子：
20.3
通讯作者：
O'Connor, Owen A.
中科院分区：
文献类型：
--
作者：
Kalac, Matko;Scotto, Luigi;O'Connor, Owen A.
在弥漫性大b细胞淋巴瘤（DLBCL）模型中研究了组蛋白去乙酰化酶抑制剂（HDACIs）和地西他滨的相互作用。采用生发中心b样细胞和活化b细胞样DLBCL细胞系、患者源性肿瘤细胞和小鼠异种移植模型，研究了HDACIs和地西他滨在该系统中的作用。所有研究均表明，HDACIs联合地西他滨在抑制DLBCL细胞生长和诱导凋亡方面具有协同作用。这种作用是时间依赖性的，通过caspase-3激活介导，并导致乙酰化组蛋白水平升高。panobinostat和地西他滨在患者源性原发肿瘤细胞中诱导细胞凋亡的协同作用得到证实。异种嫁接实验证实了该组合的体外活性和耐受性。我们通过微阵列评估基因表达和甲基化模式来分析这种协同效应的分子基础，并通过亚硫酸酯测序进行验证。这些分析表明，通过每种单一治疗条件和联合治疗确定的差异表达基因和网络是独特的，很少有重叠基因。panobinostat和地西他滨联合改变的基因有VHL、TCEB1、WT1和DIRAS3。(血。2011;118 (20):5506 - 5516)
Interactions between histone deacetylase inhibitors (HDACIs) and decitabine were investigated in models of diffuse large B-cell lymphoma (DLBCL). A number of cell lines representing both germinal center B-like and activated B-cell like DLBCL, patient-derived tumor cells and a murine xenograft model were used to study the effects of HDACIs and decitabine in this system. All explored HDACIs in combination with decitabine produced a synergistic effect in growth inhibition and induction of apoptosis in DLBCL cells. This effect was time dependent, mediated via caspase-3 activation, and resulted in increased levels of acetylated histones. Synergy in inducing apoptosis was confirmed in patient-derived primary tumor cells treated with panobinostat and decitabine. Xenografting experiments confirmed the in vitro activity and tolerability of the combination. We analyzed the molecular basis for this synergistic effect by evaluating gene-expression and methylation patterns using microarrays, with validation by bisulfite sequencing. These analyses revealed differentially expressed genes and networks identified by each of the single treatment conditions and by the combination therapy to be unique with few overlapping genes. Among the genes uniquely altered by the combination of panobinostat and decitabine were VHL, TCEB1, WT1, and DIRAS3. (Blood. 2011;118(20):5506-5516)