CRA-026440:: a potent, broad-spectrum, hydroxamic histone deacetylase inhibitor with antiproliferative and antiangiogenic activity in vitro and in vivo
CRA-026440:: a potent, broad-spectrum, hydroxamic histone deacetylase inhibitor with antiproliferative and antiangiogenic activity in vitro and in vivo
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DOI：
10.1158/1535-7163.mct-06-0042
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发表时间：
2006-07-01
影响因子：
5.7
通讯作者：
Buggy, Joseph J.
中科院分区：
文献类型：
--
作者：
Cao, Z. Alexander;Bass, Kathryn E.;Buggy, Joseph J.
CRA-026440 是一种新型广谱、基于异羟肟酸的组蛋白脱乙酰酶 (HDAC) 抑制剂，在临床前体外和体内显示出抗肿瘤和抗血管生成活性。 CRA-026440 在纳摩尔范围内抑制纯重组同工酶 HDAC1、HDAC2、HDAC3/SMRT、HDAC6、HDAC8 和 HDAC10。用 CRA-026440 处理体外培养的肿瘤细胞系会导致乙酰化组蛋白和乙酰化微管蛋白的积累，从而抑制肿瘤细胞生长并诱导细胞凋亡。 CRA026440 以剂量依赖性方式抑制离体血管生成。 CRA-026440 肠胃外给予携带 HCT116 或 U937 人类肿瘤异种移植物的小鼠；导致肿瘤生长在统计学上显着减少。 CRA-026440 与 Avastin 联合使用时，在 HCT 116 结直肠肿瘤模型中取得了更大的临床前疗效。肿瘤生长的抑制伴随着外周血单核细胞中α-微管蛋白乙酰化的增加以及肿瘤中许多基因表达的改变，包括一些与血管生成、细胞凋亡和细胞生长有关的基因。这些结果表明 CRA-026440 是一种具有有效抗肿瘤活性的新型 HDAC 抑制剂。
CRA-026440 is a novel, broad-spectrum, hydroxamic acid-based inhibitor of histone deacetylase (HDAC) that shows antitumor and antiangiogenic activities in vitro and in vivo preclinically. CRA-026440 inhibited pure recombinant isozymes HDAC1, HDAC2, HDAC3/SMRT, HDAC6, HDAC8, and HDAC10 in the nanomolar range. Treatment of cultured tumor cell lines grown in vitro with CRA-026440 resulted in the accumulation of acetylated histone and acetylated tubulin, leading to an inhibition of tumor cell growth and the induction of apoptosis. CRA026440 inhibited ex vivo angiogenesis in a dose-dependent manner. CRA-026440 parenterally given to mice harboring HCT116 or U937 human tumor xenografts; resulted in a statistically significant reduction in tumor growth. CRA-026440, when used in combination with Avastin, achieved greater preclinical efficacy in HCT 116 colorectal tumor model. Inhibition of tumor growth was accompanied by an increase in the acetylation of alpha-tubulin in peripheral blood mononuclear cells and an alteration in the expression of many genes in the tumors, including several involved in angiogenesis, apoptosis, and cell growth. These results reveal CRA-026440 to be a novel HDAC inhibitor with potent antitumor activity.