Entinostat, a novel histone deacetylase inhibitor is active in B-cell lymphoma and enhances the anti-tumour activity of rituximab and chemotherapy agents.
Entinostat, a novel histone deacetylase inhibitor is active in B-cell lymphoma and enhances the anti-tumour activity of rituximab and chemotherapy agents.
复制标题
DOI：
10.1111/bjh.13318
复制
发表时间：
2015-05
影响因子：
6.5
通讯作者：
Hernandez-Ilizaliturri FJ
中科院分区：
文献类型：
--
作者：
Frys S;Simons Z;Hu Q;Barth MJ;Gu JJ;Mavis C;Skitzki J;Song L;Czuczman MS;Hernandez-Ilizaliturri FJ
组蛋白去乙酰化酶（HDAC）抑制剂在T细胞淋巴瘤中具有活性，正在其他肿瘤中进行临床前和临床试验。恩替司他是一种口服生物可利用的I类HDAC抑制剂，半衰期长，正在血液学和实体肿瘤恶性肿瘤中进行评估。为了确定恩替司他在B细胞淋巴瘤中的活性和生物学作用，我们在几种利妥昔单抗敏感或耐药的临床前模型中研究了其抗肿瘤活性。我们证明恩替司他在利妥昔单抗敏感细胞系（RSCL）、利妥昔单抗耐药细胞系（RRCL）和从淋巴瘤患者分离的原发性肿瘤细胞（n = 36）中具有活性。恩替司他暴露降低了Bcl-XL（BCL 2L 1）水平并诱导细胞凋亡。在RSCL和RRCL中，恩替司他诱导p21（CDKN 1A）表达，导致G1细胞周期停滞，并在与硼替佐米或阿糖胞苷联合使用时表现出累加效应。半胱天冬酶抑制降低了一些原发性肿瘤细胞中的恩替司他活性，表明恩替司他具有双重作用机制。此外，恩替司他增加了CD 20和粘附分子的表达。可能与这些作用有关，我们在携带淋巴瘤的严重联合免疫缺陷（SCID）小鼠模型中观察到恩替司他和利妥昔单抗之间的协同活性。我们的数据表明恩替司他是一种活性HDAC抑制剂，可增强利妥昔单抗的体内活性，并支持其在B细胞淋巴瘤中的进一步临床开发。
Histone deacetylases (HDACs) inhibitors are active in T-cell lymphoma and are undergoing pre-clinical and clinical testing in other neoplasms. Entinostat is an orally bioavailable class I HDAC inhibitor with a long half-life, which is under evaluation in haematological and solid tumour malignancies. To define the activity and biological effects of entinostat in B-cell lymphoma we studied its anti-tumour activity in several rituximab-sensitive or -resistant pre-clinical models. We demonstrated that entinostat is active in rituximab-sensitive cell lines (RSCL), rituximab-resistant cell lines (RRCL) and primary tumour cells isolated from lymphoma patients (n = 36). Entinostat exposure decreased Bcl-XL (BCL2L1) levels and induced apoptosis in cells. In RSCL and RRCL, entinostat induced p21 (CDKN1A) expression leading to G1 cell cycle arrest and exhibited additive effects when combined with bortezomib or cytarabine. Caspase inhibition diminished entinostat activity in some primary tumour cells suggesting that entinostat has dual mechanisms-of-action. In addition, entinostat increased the expression of CD20 and adhesion molecules. Perhaps related to these effects, we observed a synergistic activity between entinostat and rituximab in a lymphoma-bearing severe combined immunodeficiency (SCID) mouse model. Our data suggests that entinostat is an active HDAC inhibitor that potentiates rituximab activity in vivo and supports its further clinical development in B-cell lymphoma.
登录
查看更多内容
影响因子：
20.3
作者：
Kalac, Matko;Scotto, Luigi;O'Connor, Owen A.
通讯作者：
O'Connor, Owen A.
影响因子：
20.3
作者：
Buglio, Daniela;Georgakis, Georgios V.;Younes, Anas
通讯作者：
Younes, Anas
影响因子：
20.3
作者：
Hiddemann, W;Kneba, M;Unterhalt, M
通讯作者：
Unterhalt, M
影响因子：
11.4
作者：
DeAngelo, D. J.;Spencer, A.;Ottmann, O. G.
通讯作者：
Ottmann, O. G.
影响因子：
45.3
作者：
Czuczman, MS;Grillo-López, AJ;Varns, C
通讯作者：
Varns, C