Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan.
Toxicol Appl Pharmacol. 2011 Nov 15;257(1):59-66. doi: 10.1016/j.taap.2011.08.018. Epub 2011 Aug 25.
The efficacy of arsenic trioxide (ATO) against acute promyelocytic leukemia (APL) and relapsed APL has been well documented. ATO may cause DNA damage by generating reactive oxygen intermediates. Suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, modulates gene and protein expression via histone-dependent or -independent pathways that may result in chromatin decondensation, cell cycle arrest, differentiation, and apoptosis. We investigated whether ATO and SAHA act synergistically to enhance the death of cancer cells. Our current findings showed that combined treatment with ATO and SAHA resulted in enhanced suppression of non-small-cell lung carcinoma in vitro in H1299 cells and in vivo in a xenograft mouse model. Flow cytometric analysis of annexin V+ cells showed that apoptotic cell death was significantly enhanced after combined treatment with ATO and SAHA. At the doses used, ATO did not interfere with cell cycle progression, but SAHA induced p21 expression and led to G1 arrest. A Comet assay demonstrated that ATO, but not SAHA, induced DNA strand breaks in H1299 cells; however, co-treatment with SAHA significantly increased ATO-induced DNA damage. Moreover, SAHA enhanced acetylation of histone H3 and sensitized genomic DNA to DNase I digestion. Our results suggest that SAHA may cause chromatin relaxation and increase cellular susceptibility to ATO-induced DNA damage. Combined administration of SAHA and ATO may be an effective approach to the treatment of lung cancer.
三氧化二砷（ATO）对急性早幼粒细胞白血病（APL）和复发性 APL 的疗效已有充分的文献记载。ATO 可能通过生成活性氧中间体导致 DNA 损伤。丁酸钠（SAHA）是一种组蛋白去乙酰化酶抑制剂，通过依赖于组蛋白或不依赖于组蛋白的途径来调节基因和蛋白质表达，这可能导致染色质去浓缩、细胞周期停滞、分化和凋亡。我们研究了 ATO 和 SAHA 是否协同作用以增强癌细胞的死亡。我们目前的研究结果表明，ATO 和 SAHA 的联合治疗可显著增强体外 H1299 细胞中非小细胞肺癌和体内异种移植小鼠模型中的抑制作用。用 Annexin V+细胞进行流式细胞术分析表明，联合 ATO 和 SAHA 治疗后，凋亡细胞死亡明显增强。在使用的剂量下，ATO 不会干扰细胞周期进程，但 SAHA 诱导 p21 表达并导致 G1 期阻滞。彗星试验表明，ATO 而非 SAHA 可诱导 H1299 细胞中的 DNA 链断裂；然而，SAHA 的联合治疗显著增加了 ATO 诱导的 DNA 损伤。此外，SAHA 增强了组蛋白 H3 的乙酰化，并使基因组 DNA 对 DNase I 消化敏感。我们的结果表明，SAHA 可能导致染色质松弛，并增加细胞对 ATO 诱导的 DNA 损伤的敏感性。SAHA 和 ATO 的联合给药可能是治疗肺癌的有效方法。
