Princess Margaret Hospital, Ontario Cancer Institute, Ontario, Canada.
Mol Cancer Ther. 2010 Jan;9(1):246-56. doi: 10.1158/1535-7163.MCT-09-0495. Epub 2010 Jan 6.
Evasion of death receptor ligand-induced apoptosis represents an important contributor to cancer development and progression. Therefore, molecules that restore sensitivity to death receptor stimuli would be important tools to better understand this biological pathway and potential leads for therapeutic adjuncts. Previously, the small-molecule 4-(4-chloro-2-methylphenoxy)-N-hydroxybutanamide (that we propose be named droxinostat) was identified as a chemical sensitizer to death receptor stimuli, decreasing the expression of the caspase-8 inhibitor FLIP. However, the direct targets of droxinostat were unknown. To better understand the mechanism of action of droxinostat and highlight new strategies to restore sensitivity to death receptor ligands, we analyzed changes in gene expression using the Connectivity Map after treating cells with droxinostat. Changes in gene expression after droxinostat treatment resembled changes observed after treatment with histone deacetylase (HDAC) inhibitors. Therefore, we examined the effects of droxinostat on HDAC activity and showed that it selectively inhibited HDAC3, HDAC6, and HDAC8 and that inhibition of these HDACs was functionally important for its ability to sensitize cells to death ligands. Thus, we have identified a selective HDAC inhibitor and showed that selective HDAC inhibition sensitizes cells to death ligands, thereby highlighting a new mechanism to overcome resistance to death receptor ligands.
逃避死亡受体配体诱导的细胞凋亡是癌症发生和发展的一个重要因素。因此，恢复对死亡受体刺激的敏感性的分子将是更好地理解这一生物学途径的重要工具，也是治疗辅助手段的潜在先导化合物。先前，小分子 4-(4-氯-2-甲基苯氧基)-N-羟基丁酰胺（我们建议将其命名为 droxinostat）被鉴定为死亡受体刺激的化学增敏剂，降低了半胱天冬酶-8 抑制剂 FLIP 的表达。然而，droxinostat 的直接靶点尚不清楚。为了更好地了解 droxinostat 的作用机制，并强调恢复对死亡受体配体敏感性的新策略，我们在用 droxinostat 处理细胞后，使用连接图谱分析了基因表达的变化。droxinostat 处理后基因表达的变化与组蛋白去乙酰化酶（HDAC）抑制剂治疗后观察到的变化相似。因此，我们研究了 droxinostat 对 HDAC 活性的影响，结果表明它选择性抑制 HDAC3、HDAC6 和 HDAC8，并且抑制这些 HDAC 对其使细胞对死亡配体敏感的能力具有功能重要性。因此，我们鉴定了一种选择性的 HDAC 抑制剂，并表明选择性的 HDAC 抑制使细胞对死亡配体敏感，从而突出了克服对死亡受体配体的耐药性的新机制。
