It's about time: Scheduling alters effect of histone deacetylase inhibitors on camptothecin-treated cells
It's about time: Scheduling alters effect of histone deacetylase inhibitors on camptothecin-treated cells
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DOI：
10.1158/0008-5472.can-05-0836
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发表时间：
2005-08-01
期刊：
影响因子：
11.2
通讯作者：
Zimmer, SG
中科院分区：
文献类型：
--
作者：
Bevins, RL;Zimmer, SG
联合药物化疗是多种癌症的一线治疗方法。联合针对不同信号通路的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。描述了一种明确的调度方案，通过该方案，组蛋白脱乙酰酶抑制剂 (HDI) 可以促进拓扑异构酶 I 抑制剂喜树碱杀死肿瘤细胞的细胞毒功效。在添加喜树碱的当天、前一天或后一天用喜树碱和丁酸钠(NaB)或辛二酰苯胺异羟肟酸处理乳腺癌和肺癌细胞系。根据添加时间的不同，NaB 处理的细胞表现出从保护到致敏的一系列反应，表明 RDI 使用时机的关键性质。如果与喜树碱后 24 至 48 小时添加的 HDI 联合使用，100 nmol/L 喜树碱的 IC80（72 小时测定）剂量可降低至 15 nmol/L 喜树碱，同时保持或超过单药的细胞杀伤作用。实验确定，被喜树碱抑制在 G(2)-M 中的细胞对随后添加的 HDI 最敏感。蛋白质印迹分析表明，在喜树碱抑制的细胞中，NaB 降低了细胞周期蛋白 B 的水平，以及抗凋亡蛋白 XIAP 和生存素的水平。这些发现表明，如果按照不阻止或抑制肿瘤细胞进入S期的顺序给药，降低这些关键抗凋亡因子的水平可能会提高临床环境中拓扑异构酶I抑制剂的疗效。
Chemotherapeutic treatment with combinations of drugs is front-line therapy for many types of cancer. Combining drugs which target different signaling pathways often lessens adverse side effects while increasing the efficacy of treatment and reducing patient morbidity. A defined scheduling protocol is described by which histone deacetylase inhibitors (HDIs) facilitate the cytotoxic effectiveness of the topoisomerase I inhibitor camptothecin in the killing of tumor cells. Breast and lung cancer cell lines were treated with camptothecin and sodium butyrate (NaB) or suberoylanilide hydroxamic acid on the day of, the day before, or the day after camptothecin addition. Depending on the time of addition, NaB-treated cells displayed a spectrum of responses from protection to sensitization, indicating the critical nature of timing in the use of RDIs. The IC80 (72-hour assay) dose of 100 nmol/L camptothecin could be lowered to 15 nmol/L camptothecin while maintaining or surpassing cell killing of the single agent if combined with an HDI added 24 to 48 hours after camptothecin. Experiments determined that cells arrested in G(2)-M by camptothecin were most sensitive to subsequent HDI addition. Western blot analysis indicated that in camptothecin-arrested cells, NaB decreases cyclin B levels, as well as the levels of the antiapoptotic proteins XIAP and survivin. These findings suggest that reducing the levels of these critical antiapoptotic factors may increase the efficacy of topoisomerase I inhibitors in the clinical setting if given in a sequence that does not prevent or inhibit tumor cell progression through the S phase.