Sequence-dependent interaction between cisplatin and histone deacetylase inhibitors in human oral squamous cell carcinoma cells.
Sequence-dependent interaction between cisplatin and histone deacetylase inhibitors in human oral squamous cell carcinoma cells.
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DOI：
10.3892/ijo.28.5.1233
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发表时间：
2006-05
影响因子：
5.2
通讯作者：
Tomonori Sato;Maiko Suzuki;Y. Sato;S. Echigo;H. Rikiishi
中科院分区：
文献类型：
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作者：
Tomonori Sato;Maiko Suzuki;Y. Sato;S. Echigo;H. Rikiishi
联合用药的化疗是许多癌症的一线治疗。针对不同信号通路的联合药物通常可以减少不良副作用，同时提高治疗效果并降低患者发病率。组蛋白去乙酰化酶（HDAC）抑制剂代表一类新型抗肿瘤剂，其通过促进核心组蛋白的乙酰化而起作用，进而导致染色质的解螺旋和涉及细胞存活、增殖、分化和凋亡的调节的多种基因的激活。一个定义的调度协议，HDAC抑制剂促进顺铂（CDDP）在杀死癌细胞的细胞毒性的有效性。在加入CDDP的当天、前一天或后一天，用丁酸钠（NaB）、辛二酰苯胺异羟肟酸（SAHA）或MS-275处理口腔鳞状细胞癌细胞系（HSC-3）。当与HDAC抑制剂（MS-275）同时组合时，3.48 μ g/ml CDDP的IC 50（48小时测定）值可降低至0.41 μ g/ml CDDP。CDDP处理24小时，然后NaB再处理24小时而不洗涤的细胞凋亡百分比显著大于以相反顺序观察到的百分比。根据加入HDAC抑制剂的时间，CDDP处理的细胞显示出不同程度的凋亡反应，表明HDAC抑制剂使用时机的关键性质。有趣的是，实验表明，被CDDP阻滞在G1/S检查点的细胞对随后用HDAC抑制剂处理更敏感。此外，这些事件与HDAC抑制剂增强活性氧（ROS）生成和caspase-3激活有关。他们提出的可能性，结合这些药物可能代表一种新的抗肿瘤策略。
Chemotherapeutic treatment with combinations of drugs is front-line therapy for many types of cancer. Combining drugs that target different signaling pathways often lessens adverse side-effects while increasing the efficacy of treatment and reducing patient morbidity. Histone deacetylase (HDAC) inhibitors represent a novel class of anti-neoplastic agents that act by promoting acetylation of core histones, leading in turn to the uncoiling of chromatin and activation of a variety of genes implicated in the regulation of cell survival, proliferation, differentiation, and apoptosis. A defined scheduling protocol is described by which HDAC inhibitors facilitate the cytotoxic effectiveness of cisplatin (CDDP) in the killing of carcinoma cells. An oral squamous cell carcinoma cell line (HSC-3) was treated with sodium butyrate (NaB), suberoylanilide hydroxamic acid (SAHA) or MS-275 on the day of, the day before, or the day after addition of CDDP. The IC50 (48-h assay) value of 3.48 microg/ml CDDP could be lowered to 0.41 microg/ml CDDP when concurrently combined with an HDAC inhibitor (MS-275). The percentage of apoptosis by treatment with CDDP for 24 h, followed by NaB for an additional 24 h without washing was significantly greater than that observed in the reverse order. Depending on the time of addition of HDAC inhibitors, CDDP-treated cells displayed varying degrees of apoptotic responses, indicating the critical nature of timing in the use of HDAC inhibitors. Interestingly, experiments suggested that cells arrested at the G1/S checkpoint by CDDP were more sensitive to subsequent treatment with an HDAC inhibitor. Moreover, these events were associated with an enhancement of reactive oxygen species (ROS) generation and caspase-3 activation by HDAC inhibitors. They raise the possibility that combining these agents may represent a novel anti-neoplastic strategy.