Portanova Patrizia, Russo Tiziana, Pellerito Ornella, Calvaruso Giuseppe, Giuliano Michela, Vento Renza, Tesoriere Giovanni
Dipartimento di Scienze Biochimiche, Università degli Studi di Palermo, 90127 Palermo, Italy.
Int J Oncol. 2008 Aug;33(2):325-31.
Histone deacetylase inhibitors (HDACIs) activate genes that promote cell cycle arrest and apoptosis in a number of tumor cells. This study showed that suberoylanilide hydroxamic acid (SAHA), a potent and commonly used HDACI, induced apoptosis in human colon adenocarcinoma HT-29 cells in a time- and dose-dependent manner. This effect was accompanied by the induction of oxidative stress, dissipation of mitochondrial transmembrane potential and activation of executioner caspases. Moreover, SAHA increased the levels of phosphorylated active forms of p38 and JNK. The addition of either the antioxidant N-acetylcysteine or the specific inhibitor of NADPH oxidase diphenylene iodonium chloride reduced the cytotoxic effects of SAHA in HT-29 cells, suggesting that the induction of oxidative stress represents a crucial event in the apoptotic mechanism. In addition, SAHA up-regulated the death receptor DR5, inducing the activation of caspase-8 with the consequent cleavage of Bid. Furthermore, SAHA down-regulated FLIPL and Akt, two proteins which exert an inhibitory role in apoptosis.
组蛋白去乙酰化酶抑制剂（HDACIs）可激活一些促进多种肿瘤细胞发生细胞周期阻滞和凋亡的基因。本研究表明，一种强效且常用的HDACI——辛二酰苯胺异羟肟酸（SAHA），可呈时间和剂量依赖性地诱导人结肠腺癌HT - 29细胞凋亡。这种效应伴随着氧化应激的诱导、线粒体跨膜电位的消散以及执行半胱天冬酶的激活。此外，SAHA增加了p38和JNK磷酸化活性形式的水平。添加抗氧化剂N - 乙酰半胱氨酸或NADPH氧化酶特异性抑制剂二亚苯基碘鎓氯化物均可降低SAHA对HT - 29细胞的细胞毒性作用，这表明氧化应激的诱导是凋亡机制中的一个关键事件。此外，SAHA上调死亡受体DR5，诱导半胱天冬酶 - 8的激活，进而导致Bid的裂解。此外，SAHA下调FLIPL和Akt，这两种蛋白在凋亡中发挥抑制作用。
