组蛋白去乙酰化酶抑制剂诱导肿瘤细胞凋亡的机制

The Mechanism of Apoptosis Induced by Histone Deacetylase Inhibitors

组蛋白去乙酰化酶抑制剂(HDACi)是一类新的化疗药物,能够有效抑制组蛋白去乙酰化酶的活性,促进组蛋白及非组蛋白的乙酰化修饰,在转录和翻译后修饰水平调控肿瘤靶蛋白及凋亡相关蛋白的表达和降解,活化凋亡信号通路,诱导肿瘤细胞凋亡。HDACi抑制抗氧化蛋白的表达,提高细胞内活性氧的水平,引起细胞的氧化损伤。因此,氧化损伤诱导的细胞凋亡也是HDACi杀伤肿瘤细胞的重要机制。HDACi诱导细胞凋亡机制的发现将进一步促进HDACi在临床治疗中的应用。

Histone deacetylase inhibitors（HDACi） are new generation of chemotherapeutic agents, which induce acetyla- tion of histone proteins and non-histone proteins by inhibiting the activity of histone deacetylase. As acetylation of proteins facilitates the expression of proapoptotic genes and induces the degradation of oncoproteins and antiapoptotic proteins, HDACi induce apoptosis by activating the apoptotic signal transduction pathways at transcription and posttranslation levels. HDACi also induce accumulation of reactive oxygen species （ROS） by suppressing the expression of antioxidant proteins. The abberant ROS induce oxidative damage which activates mitochondrial-mediated apoptotic signal transduction pathway, so HDACi also induce apoptosis by causing oxidative damage. Therefore, many kinds of mechanisms were involved in the regulation of HDACi-induced apoptosis, which promote the development of HDACi in clinical trials.