Beckers Thomas, Burkhardt Carmen, Wieland Heike, Gimmnich Petra, Ciossek Thomas, Maier Thomas, Sanders Karl
Therapeutic Area Oncology, ALTANA Pharma-a member of the Nycomed Group, Byk-Gulden Street 2, 78467 Konstanz, Germany. Thomas.Beckers.com
Int J Cancer. 2007 Sep 1;121(5):1138-48. doi: 10.1002/ijc.22751.
Advanced second generation inhibitors of histone deacetylases (HDAC) are currently used in clinical development. This study aimed at comparing the pharmacological properties of selected second generation HDAC inhibitors with the hydroxamate and benzamide head group, namely SAHA, LAQ824/LBH589, CI994, MS275 and MGCD0103. In biochemical assays using recombinant HDAC1, 3, 6 and 8 isoenzymes, SAHA and LAQ824/LBH589 behave as quite unselective HDAC inhibitors. In contrast, the benzamides CI994, MS275 and MGCD0103 are more selective, potent inhibitors of at least HDAC1 and HDAC3. All HDAC inhibitors induce histone H3 hyperacetylation, correlating with inhibition of proliferation, induction of cell differentiation and apoptosis. A broad cytotoxicity is seen across cell lines from different tumor entities with LAQ824/LBH589 being the most potent agents. The apoptosis inducing activity is evident in arrested and proliferating RKO colon cancer cells with inducible, heterologous p21(waf1) expression, indicative for a cell-cycle independent mode-of-action. Differentiation of MDA-MB468 breast cancer cells is induced by benzamide and hydroxamate analogs. The reversibility of drug action was evaluated by pulse treatment of A549 lung cancer cells. Whereas paclitaxel induced irreversible cell cycle alterations already after 6 hr treatment, HDAC inhibitor action was retarded and irreversible after >16 hr treatment. Interestingly, pulse treatment was equally effective as continous treatment. Finally, the efficacy of LAQ824, SAHA and MS275 in A549 nude mice xenografts was comparable to that of paclitaxel at well tolerated doses. We conclude that despite a different HDAC isoenzyme inhibition profile, hydroxamate and benzamide analogs as studied display similar cellular profiles.
先进的第二代组蛋白去乙酰化酶（HDAC）抑制剂目前正处于临床开发阶段。本研究旨在比较选定的具有异羟肟酸酯和苯甲酰胺头部基团的第二代HDAC抑制剂的药理学特性，即SAHA、LAQ824/LBH589、CI994、MS275和MGCD0103。在使用重组HDAC1、3、6和8同工酶的生化分析中，SAHA和LAQ824/LBH589表现为相当非选择性的HDAC抑制剂。相比之下，苯甲酰胺类CI994、MS275和MGCD0103是更具选择性、对至少HDAC1和HDAC3有效的抑制剂。所有HDAC抑制剂均诱导组蛋白H3高度乙酰化，这与增殖抑制、细胞分化诱导和细胞凋亡相关。在来自不同肿瘤实体的细胞系中观察到广泛的细胞毒性，其中LAQ824/LBH589是最有效的药物。凋亡诱导活性在具有可诱导的、异源p21（waf1）表达的停滞和增殖的RKO结肠癌细胞中明显，这表明其作用模式不依赖于细胞周期。苯甲酰胺和异羟肟酸酯类似物可诱导MDA-MB468乳腺癌细胞分化。通过对A549肺癌细胞进行脉冲处理来评估药物作用的可逆性。紫杉醇在处理6小时后就诱导了不可逆的细胞周期改变，而HDAC抑制剂的作用在处理超过16小时后才延迟且不可逆。有趣的是，脉冲处理与连续处理同样有效。最后，LAQ824、SAHA和MS275在A549裸鼠异种移植瘤中的疗效在耐受良好的剂量下与紫杉醇相当。我们得出结论，尽管HDAC同工酶抑制谱不同，但所研究的异羟肟酸酯和苯甲酰胺类似物表现出相似的细胞特性。
