Institute for Experimental Cancer Research in Pediatrics, Goethe-University Frankfurt, Frankfurt, Germany.
Exp Cell Res. 2012 Jul 1;318(11):1208-12. doi: 10.1016/j.yexcr.2012.02.005. Epub 2012 Feb 15.
Evasion of apoptosis represents a key mechanism leading to treatment resistance of human cancers. Abnormal regulation of chromatin remodeling has been implied in tumorigenesis as well as treatment resistance. Acetylation of histones represents one of the key posttranslational modifications that contribute to the regulation of chromatin remodeling. Histone acetylation is governed by the balance between enzymes that put acetyl groups on histone tails or, alternatively, remove them. Since a disturbed regulation of histone acetylation plays an important role in cancer formation and progression, a variety of histone deacetylase (HDAC) inhibitors have been developed in recent years to target aberrant HDAC activity. HDAC inhibitors also represent a promising strategy to lower the threshold of cancer cells for apoptosis induction. For example, synergistic induction of apoptosis has been documented for the concomitant use of HDAC inhibitors together with the death receptor ligand TRAIL in a panel of human cancers. Understanding the molecular mechanism that mediates this synergistic drug interaction will be critical to further optimize this approach in order to successfully translate it into a clinical setting.
细胞凋亡逃逸是导致人类癌症治疗抵抗的关键机制。染色质重塑的异常调节与肿瘤发生以及治疗抵抗有关。组蛋白乙酰化是一种关键的翻译后修饰，有助于调节染色质重塑。组蛋白乙酰化受将乙酰基添加到组蛋白尾部的酶或相反地去除它们的酶之间的平衡控制。由于组蛋白乙酰化的失调调节在癌症的形成和进展中起着重要作用，近年来已经开发了多种组蛋白去乙酰化酶 (HDAC) 抑制剂来靶向异常的 HDAC 活性。HDAC 抑制剂也代表了降低癌细胞凋亡诱导阈值的有前途的策略。例如，在一系列人类癌症中，同时使用 HDAC 抑制剂和死亡受体配体 TRAIL 已证明协同诱导细胞凋亡。了解介导这种协同药物相互作用的分子机制对于进一步优化这种方法以成功将其转化为临床环境至关重要。
