Sato Tomonori, Suzuki Maiko, Sato Yoshitaro, Echigo Seishi, Rikiishi Hidemi
Department of Microbiology and Immunology, Tohoku University Graduate School of Dentistry, Aoba-ku, Sendai 980-8575, Japan.
Int J Oncol. 2006 May;28(5):1233-41.
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.
联合使用多种药物进行化疗是多种癌症的一线治疗方法。将针对不同信号通路的药物联合使用，通常可以减少不良反应，同时提高治疗效果并降低患者的发病率。组蛋白去乙酰化酶（HDAC）抑制剂是一类新型抗肿瘤药物，其作用机制是促进核心组蛋白的乙酰化，进而导致染色质解旋，并激活与细胞存活、增殖、分化和凋亡调控相关的多种基因。本文描述了一种特定的给药方案，通过该方案，HDAC抑制剂可增强顺铂（CDDP）对癌细胞的杀伤效果。在添加CDDP的当天、前一天或后一天，使用丁酸钠（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）同时联合使用时，3.48μg/ml CDDP的IC50（48小时检测）值可降至0.41μg/ml CDDP。先用CDDP处理24小时，然后不清洗直接用NaB再处理24小时，这种处理方式诱导的凋亡百分比显著高于相反顺序处理时观察到的凋亡百分比。根据HDAC抑制剂添加的时间不同，经CDDP处理的细胞表现出不同程度的凋亡反应，这表明在使用HDAC抑制剂时给药时间至关重要。有趣的是，实验表明，被CDDP阻滞在G1/S期检查点的细胞对随后的HDAC抑制剂治疗更敏感。此外，这些事件与HDAC抑制剂增强活性氧（ROS）生成和激活caspase-3有关。这增加了联合使用这些药物可能代表一种新型抗肿瘤策略的可能性。
