Department of Lymphoma and Myeloma, The University of Texas M.D. Anderson Cancer Center, Houston, USA.
Exp Hematol. 2011 Oct;39(10):1007-1017.e1. doi: 10.1016/j.exphem.2011.07.002. Epub 2011 Jul 20.
Based on promising in vitro and in vivo activity of several histone deacetylase inhibitors in Hodgkin lymphoma (HL), we investigated SNDX-275, an oral class 1 isoform-selective histone deacetylase inhibitors in HL-derived cell lines.
Proliferation and cell death were examined by MTS assay, Annexin V/propidium iodide, and fluorescence-activated cell sorting analysis. Gene and protein expression were measured by reverse transcriptase polymerase chain reaction, Western blotting, and immunohistochemical analysis. A multiplex assay was used to determine cytokines and chemokines.
SNDX-275 induced cell death in a dose- and time-dependent manner with an IC(50) at the sub- and lower micromolar range at 72 hours. At the molecular level, SNDX-275 increased histone H3 acetylation, upregulated p21 expression, and activated the intrinsic apoptosis pathway by downregulating the X-linked inhibitor of apoptosis protein. SNDX-275 downregulated expression of antiapoptotic Bcl-2 and Bcl-xL proteins without altering Mcl-1 or Bax levels. Combination studies demonstrated that two Bcl-2 inhibitors (ABT-737 and obatoclax) significantly enhanced the effect of SNDX-275. SNDX-275 modulated the level of several cytokines and chemokines, including interleukin-12 p40-70, interferon-inducible protein-10, RANTES (regulated on activation, normal T expressed and secreted), interleukin-13, interleukin-4, and thymus and activation-regulated chemokine and variably induced the cancer/testis antigen expression of MAGE-A4 and survivin in HL cell lines.
SNDX-275 has antiproliferative activity in HL cell lines, involving several mechanisms: induction of apoptosis, regulation of cytokines and chemokines, and alteration of cancer/testis antigens. Clinical investigation of SNDX-275 alone or in combination with Bcl-2 inhibitors is warranted in patients with HL. Phase 2 studies with SNDX-275 in HL are ongoing, and future clinical studies should investigate combinations with SNDX-275.
基于几种组蛋白去乙酰化酶抑制剂在霍奇金淋巴瘤（HL）中的体外和体内活性，我们研究了 SNDX-275，一种口服的 1 类同工酶选择性组蛋白去乙酰化酶抑制剂，在 HL 衍生细胞系中的作用。
通过 MTS 检测、Annexin V/碘化丙啶和荧光激活细胞分选分析检测增殖和细胞死亡。通过逆转录聚合酶链反应、Western 印迹和免疫组织化学分析测量基因和蛋白质表达。使用多重测定法测定细胞因子和趋化因子。
SNDX-275 以剂量和时间依赖性方式诱导细胞死亡，72 小时时的 IC50 值处于亚微摩尔和较低微摩尔范围内。在分子水平上，SNDX-275 增加组蛋白 H3 乙酰化，上调 p21 表达，并通过下调 X 连锁凋亡抑制蛋白激活内在凋亡途径。SNDX-275 下调抗凋亡 Bcl-2 和 Bcl-xL 蛋白的表达，而不改变 Mcl-1 或 Bax 水平。组合研究表明，两种 Bcl-2 抑制剂（ABT-737 和 obatoclax）显著增强了 SNDX-275 的作用。SNDX-275 调节了几种细胞因子和趋化因子的水平，包括白细胞介素-12 p40-70、干扰素诱导蛋白-10、调节激活正常 T 细胞表达和分泌的趋化因子（RANTES）、白细胞介素-13、白细胞介素-4 和胸腺激活调节趋化因子，并可变地诱导 HL 细胞系中癌症/睾丸抗原 MAGE-A4 和 survivin 的表达。
SNDX-275 在 HL 细胞系中具有抗增殖活性，涉及多种机制：诱导凋亡、调节细胞因子和趋化因子以及改变癌症/睾丸抗原。在 HL 患者中单独使用 SNDX-275 或与 Bcl-2 抑制剂联合使用的临床研究是合理的。SNDX-275 在 HL 中的 2 期研究正在进行中，未来的临床研究应调查 SNDX-275 与其他药物的联合应用。
