Singh Thiyam Ramsing, Shankar Sharmila, Srivastava Rakesh K
Department of Pharmaceutical Sciences, Molecular and Cellular Biology Program, Greenebaum Cancer Center, University of Maryland, Baltimore, MD 21201-1180, USA.
Oncogene. 2005 Jul 7;24(29):4609-23. doi: 10.1038/sj.onc.1208585.
Histone deacetylase (HDAC) inhibitors induce differentiation and/or apoptosis in a variety of cell types by activating transcription of target genes. Activation of the death receptor (DR) pathway by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis preferentially in cancer cells. Here, we investigated the intracellular mechanisms by which HDAC inhibitors (suberoylanilide hydroxamic acid, m-carboxycinnamic acid bis-hydroxamide, MS-275 and trichostatin A) enhance the apoptosis-inducing potential of TRAIL in breast cancer cells in vitro. A synergism in apoptosis was observed in both TRAIL-sensitive and -resistant cells upon sequential treatments with HDAC inhibitors followed by TRAIL. HDAC inhibitors synergized with TRAIL by inducing DRs DR4/TRAIL-R1 and DR5/TRAIL-R2 through NFkappaB activation and some of the proapoptotic members of the Bcl-2 family, and engaging the mitochondrial pathway. The ability of HDAC inhibitors to sensitize TRAIL-resistant cells suggests that HDAC inhibitors may induce fundamental alterations in cell signaling pathways. Thus, the sequential treatments with HDAC inhibitors followed by TRAIL may be used as a new therapeutic approach for the treatment of human cancers.
组蛋白去乙酰化酶（HDAC）抑制剂通过激活靶基因转录在多种细胞类型中诱导分化和/或凋亡。肿瘤坏死因子相关凋亡诱导配体（TRAIL）激活死亡受体（DR）途径可优先诱导癌细胞凋亡。在此，我们研究了HDAC抑制剂（辛二酰苯胺异羟肟酸、间羧基肉桂酸双羟肟酸、MS-275和曲古抑菌素A）在体外增强TRAIL诱导乳腺癌细胞凋亡潜力的细胞内机制。在用HDAC抑制剂随后用TRAIL进行序贯处理后，在TRAIL敏感和耐药细胞中均观察到凋亡协同作用。HDAC抑制剂通过激活NFκB诱导DRs DR4/TRAIL-R1和DR5/TRAIL-R2以及Bcl-2家族的一些促凋亡成员，并参与线粒体途径，从而与TRAIL产生协同作用。HDAC抑制剂使TRAIL耐药细胞致敏的能力表明，HDAC抑制剂可能会诱导细胞信号通路发生根本性改变。因此，先用HDAC抑制剂随后用TRAIL进行序贯处理可作为治疗人类癌症的一种新的治疗方法。
