The combination of hypomethylating agents and histone deacetylase inhibitors produce marked synergy in preclinical models of T-cell lymphoma
The combination of hypomethylating agents and histone deacetylase inhibitors produce marked synergy in preclinical models of T-cell lymphoma
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DOI：
10.1111/bjh.13566
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发表时间：
2015-10-01
影响因子：
6.5
通讯作者：
O'Connor, Owen A.
中科院分区：
文献类型：
--
作者：
Marchi, Enrica;Zullo, Kelly M.;O'Connor, Owen A.
t细胞淋巴瘤（TCL）是侵袭性淋巴瘤，通常采用CHOP（环磷酰胺、阿霉素、长春新碱、强的松龙）样方案进行前期治疗。最近的数据表明，TCL是由表观遗传缺陷驱动的，这可能使它们对表观遗传治疗敏感。我们探索了使用组蛋白去乙酰化酶抑制剂（HDACIs）和DNA甲基转移酶抑制剂（DNMT）在体外和体内TCL模型中的联合表观遗传平台的治疗优点。50%的抑制浓度（IC50）值显示罗米地辛是最有效的HDACI， IC50在低纳摩尔范围内。与低甲基化剂结合可在所有细胞系中产生协同作用，这在细胞毒性和凋亡实验中得到证实。一项体内异种移植研究表明，与单一药物相比，联合用药对肿瘤生长有抑制作用。基因表达阵列和全局甲基化分析揭示了每种单一处理条件和组合处理条件下差异表达的基因和调节途径。在联合用药组中，单药治疗的效果基本维持不变。总共有944个独特基因被联合处理调节，支持分子协同作用的假设。这些数据表明，在TCL模型中，低甲基化剂和hdac的组合具有协同作用，这在分子水平上得到了支持。
T-cell lymphomas (TCL) are aggressive lymphomas usually treated with CHOP (cyclophsophamide, doxorubicin, vincristine, prednisolone)-like regimens upfront. Recent data suggest that TCL are driven by epigenetic defects, potentially rendering them sensitive to epigenetic therapies. We explored the therapeutic merits of a combined epigenetic platform using histone deacetylase inhibitors (HDACIs) and DNA methyltransferase inhibitors (DNMT) in in vitro and in vivo models of TCL. The 50% inhibitory concentration (IC50) values revealed romidepsin was the most potent HDACI, with an IC50 in the low nanomolar range. The combination with a hypomethylating agent produced synergy across all cell lines, which was confirmed in cytotoxicity and apoptosis assays. An in vivo xenograft study demonstrated inhibition of tumour growth in the combination cohort compared to the single agent. Gene expression array and global methylation profiling revealed differentially expressed genes and modulated pathways for each of the single treatment conditions and the combination. Most of the effects induced by the single agent treatment were maintained in the combination group. In total, 944 unique genes were modulated by the combination treatment, supporting the hypothesis of molecular synergism. These data suggest combinations of hypomethylating agents and HDACIs are synergistic in models of TCL, which is supported at the molecular level.