Department of Obstetrics and Gynecology, Meharry Medical College, Vanderbilt University School of Medicine, Nashville, TN, USA.
Cancer Biol Ther. 2010 Jun 1;9(11):928-35. doi: 10.4161/cbt.9.11.11873. Epub 2010 Jun 25.
Histone deacetylase (HDAC) inhibitors have shown preclinical efficacy in solid tumors, including ovarian cancers. Our group has published that the HDAC inhibitor, romidepsin (FK228) suppresses ovarian cancer cell growth at nanomolar concentrations in vitro. HDAC inhibitors appear to be even more effective when used in combination with other antitumor agents. However, it remains unclear which antitumor agents are best suited for combination therapy. A recent report suggested that aspirin (acetylsalicylic acid, ASA ) is synergistic with HDAC inhibitors in ovarian cancer cells. ASA is a relatively selective inhibitor of cyclooxygenase-1 (COX-1) and has anti-proliferative effects in ovarian cancer cells. The goal of this study was to investigate the impact of ASA on the activity of the HDAC inhibitor, FK228 in COX-1 positive (OVCAR-3) and COX-1 negative (SKOV-3) human ovarian cancer cell lines. The growth inhibitory effects of FK228 were enhanced by ASA in COX-1 positive ovarian cancer cells. In contrast, ASA had no influence on the results of FK228 treatment in COX-1 negative ovarian cancer cells. Upregulation of the cell cycle control protein p21 was induced robustly by FK228 in both cell lines. In the COX-1 positive cells, p21 expression was augmented by the addition of ASA to FK228 treatment. Furthermore, COX-1 siRNA attenuated the effects of combined ASA and FK228 on the levels of p21 expression and the amount of growth inhibition. The additional increase in p21 by ASA in FK228-treated cells was not observed at the promoter or transcriptional levels. However, a significant delay in p21 protein degradation in the presence of ASA and FK228 in COX-1 positive cells was associated with inhibition of proteasome activity. Our study provides a potential rationale for combining ASA with HDAC inhibitors in a subset of ovarian cancers.
组蛋白去乙酰化酶（HDAC）抑制剂在实体瘤，包括卵巢癌中显示出临床前疗效。我们的小组已经发表了 HDAC 抑制剂罗米地辛（FK228）以纳摩尔浓度在体外抑制卵巢癌细胞生长。当与其他抗肿瘤药物联合使用时，HDAC 抑制剂似乎更有效。然而，仍然不清楚哪种抗肿瘤药物最适合联合治疗。最近的一份报告表明，阿司匹林（乙酰水杨酸，ASA）与卵巢癌细胞中的 HDAC 抑制剂具有协同作用。ASA 是环氧化酶-1（COX-1）的相对选择性抑制剂，在卵巢癌细胞中有抗增殖作用。本研究的目的是研究 ASA 对 COX-1 阳性（OVCAR-3）和 COX-1 阴性（SKOV-3）人卵巢癌细胞系中 HDAC 抑制剂 FK228 活性的影响。ASA 增强了 COX-1 阳性卵巢癌细胞中 FK228 的生长抑制作用。相比之下，ASA 对 COX-1 阴性卵巢癌细胞中 FK228 治疗结果没有影响。FK228 在两种细胞系中均强烈诱导细胞周期控制蛋白 p21 的上调。在 COX-1 阳性细胞中，ASA 与 FK228 联合治疗可增强 p21 的表达。此外，COX-1 siRNA 减弱了 ASA 和 FK228 联合对 p21 表达水平和生长抑制程度的影响。在 FK228 处理的细胞中，ASA 额外增加的 p21 未在启动子或转录水平上观察到。然而，在 COX-1 阳性细胞中，在 ASA 和 FK228 存在下，p21 蛋白降解的明显延迟与蛋白酶体活性的抑制有关。我们的研究为在卵巢癌的一部分中联合使用 ASA 和 HDAC 抑制剂提供了潜在的依据。
