Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York, USA.
Clin Cancer Res. 2010 Jan 15;16(2):554-65. doi: 10.1158/1078-0432.CCR-09-1937. Epub 2010 Jan 12.
Romidepsin and belinostat are inhibitors of histone deacetylases (HDACI). HDACIs are known to induce cell death in malignant cells through multiple mechanisms, including upregulation of death receptors and induction of cell cycle arrest. They are also known to be prodifferentiating. Mantle cell lymphoma (MCL) is an aggressive subtype of non-Hodgkin lymphoma characterized by the t(11;14)(q13;q32) translocation leading to the overexpression of cyclin D1.
Assays for cytotoxicty including mathematical analysis for synergism, flow-cytometry, immunoblottings, and a xenograft severe combined immunodeficient beige mouse model were used to explore the in vitro and in vivo activity of romidepsin and/or belinostat alone or in combination with the proteasome inhibitor bortezomib in MCL.
In vitro, romidepsin and belinostat exhibited concentration-dependent cytotoxicity against a panel of MCL cell lines. Both HDACI showed strong synergism when combined with the proteasome inhibitor bortezomib in MCL. An HDACI plus bortezomib also induced potent mitochondrial membrane depolarization and apoptosis, whereas no significant apoptosis was observed in peripheral blood mononuclear cells from healthy donors with the combination. These events were associated with a decrease in cyclin D1 and Bcl-X(L), and an increase in accumulation of acetylated histone H3, acetylated alpha-tubulin, and Noxa in cell lines. In a severe combined immunodeficient beige mouse model of MCL, the addition of belinostat to bortezomib enhanced efficacy compared with either drug alone.
Collectively, these data strongly suggest that HDACI such as romidepsin or belinostat in combination with a proteasome inhibitor could represent a novel and rationale platform for the treatment of MCL.
罗米地辛和贝林司他是组蛋白去乙酰化酶（HDACI）抑制剂。已知 HDACI 通过多种机制诱导恶性细胞死亡，包括上调死亡受体和诱导细胞周期停滞。它们也被认为是促进分化的。套细胞淋巴瘤（MCL）是一种侵袭性非霍奇金淋巴瘤亚型，其特征是 t（11;14）（q13;q32）易位导致 cyclin D1 的过表达。
使用细胞毒性测定法（包括协同作用的数学分析、流式细胞术、免疫印迹和异种移植严重联合免疫缺陷 beige 小鼠模型）来探索罗米地辛和/或贝林司他单独或与蛋白酶体抑制剂硼替佐米联合在 MCL 中的体外和体内活性。
在体外，罗米地辛和贝林司他对一系列 MCL 细胞系表现出浓度依赖性细胞毒性。两种 HDACI 与蛋白酶体抑制剂硼替佐米联合在 MCL 中表现出强烈的协同作用。HDACI 加硼替佐米也诱导了强烈的线粒体膜去极化和凋亡，而在健康供体的外周血单核细胞中观察到组合没有明显的凋亡。这些事件与 cyclin D1 和 Bcl-X(L) 的减少以及细胞系中乙酰化组蛋白 H3、乙酰化微管蛋白和 Noxa 的积累增加有关。在 MCL 的严重联合免疫缺陷 beige 小鼠模型中，与单独使用任一药物相比，贝林司他联合硼替佐米可增强疗效。
总的来说，这些数据强烈表明，罗米地辛或贝林司他等 HDACI 与蛋白酶体抑制剂联合使用可能代表治疗 MCL 的一种新的合理平台。
