文章：

罗米地辛靶向恶性T细胞中的多个生存信号通路

Romidepsin targets multiple survival signaling pathways in malignant T cells

原文发布日期：2015-10-16

DOI: 10.1038/bcj.2015.83

类型: Original Article

开放获取: 是

英文摘要：

Romidepsin is a cyclic molecule that inhibits histone deacetylases. It is Food and Drug Administration-approved for treatment of cutaneous and peripheral T-cell lymphoma, but its precise mechanism of action against malignant T cells is unknown. To better understand the biological effects of romidepsin in these cells, we exposed PEER and SUPT1 T-cell lines, and a primary sample from T-cell lymphoma patient (Patient J) to romidepsin. We then examined the consequences in some key oncogenic signaling pathways. Romidepsin displayed IC50 values of 10.8, 7.9 and 7.0 nm in PEER, SUPT1 and Patient J cells, respectively. Strong inhibition of histone deacetylases and demethylases, increased production of reactive oxygen species and decreased mitochondrial membrane potential were observed, which may contribute to the observed DNA-damage response and apoptosis. The stress-activated protein kinase/c-Jun N-terminal kinase signaling pathway and unfolded protein response in the endoplasmic reticulum were activated, whereas the phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) and β-catenin pro-survival pathways were inhibited. The decreased level of β-catenin correlated with the upregulation of its inhibitor SFRP1 through romidepsin-mediated hypomethylation of its gene promoter. Our results provide new insights into how romidepsin invokes malignant T-cell killing, show evidence of its associated DNA hypomethylating activity and offer a rationale for the development of romidepsin-containing combination therapies.

摘要翻译： 

罗米地辛是一种抑制组蛋白去乙酰化酶的环状分子，已获美国食品药品监督管理局批准用于治疗皮肤性及外周T细胞淋巴瘤，但其作用于恶性T细胞的确切机制尚未明确。为深入探究罗米地辛对该类细胞的生物学效应，我们将PEER和SUPT1 T细胞系以及一例T细胞淋巴瘤患者（患者J）的原代样本置于罗米地辛环境中，进而观察若干关键致癌信号通路的变化。罗米地辛在PEER、SUPT1和患者J细胞中的IC50值分别为10.8、7.9和7.0纳米。研究观察到组蛋白去乙酰化酶和去甲基化酶的强烈抑制、活性氧簇生成增加及线粒体膜电位降低，这些现象可能与观察到的DNA损伤应答及细胞凋亡相关。应激激活蛋白激酶/c-Jun氨基末端激酶信号通路和内质网未折叠蛋白应答被激活，而磷脂酰肌醇3-激酶/AKT/哺乳动物雷帕霉素靶蛋白（PI3K/AKT/mTOR）通路及β-连环蛋白促存活通路则受到抑制。β-连环蛋白水平下降与其抑制剂SFRP1的上调相关，后者通过罗米地辛介导的基因启动子低甲基化实现。本研究为阐释罗米地辛诱导恶性T细胞死亡的机制提供了新视角，揭示了其相关的DNA低甲基化活性证据，并为开发含罗米地辛的联合治疗方案提供了理论依据。

原文链接：

Romidepsin targets multiple survival signaling pathways in malignant T cells