Yang Ya-Ting, Balch Curt, Kulp Samuel K, Mand Michael R, Nephew Kenneth P, Chen Ching-Shih
Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
Neoplasia. 2009 Jun;11(6):552-63, 3 p following 563. doi: 10.1593/neo.09204.
Histone deacetylase inhibitors (HDACIs) are a class of antineoplastic agents previously demonstrating preclinical chemosensitizing activity against drug-resistant cancer cells and mouse xenografts. However, whereas clinical studies have shown efficacy against human hematologic malignancies, solid tumor trials have proved disappointing. We previously developed a novel HDACI, "OSU-HDAC42," and herein examine its activity against ovarian cancer cell lines and xenografts. OSU-HDAC42, (i) unlike most HDACIs, elicited a more than five-fold increase in G(2)-phase cells, at 2.5 microM, with G(2) arrest followed by apoptosis; (ii) at 1.0 microM, completely repressed messenger RNA expression of the cell cycle progression gene cdc2; (iii) at low doses (0.25-1.0 microM for 24 hours), induced tumor cell epithelial differentiation, as evidenced by morphology changes and a more than five-fold up-regulation of epithelium-specific cytokeratins; (iv) potently abrogated the growth of numerous ovarian cancer cells, with IC(50) values of 0.5 to 1.0 microM, whereas also remaining eight-fold less toxic (IC(50) of 8.6 microM) to normal ovarian surface epithelial cells; and (v) chemosensitizated platinum-resistant mouse xenografts to cisplatin. Compared with the clinically approved HDACI suberoylanilide hydroxamic acid (vorinostat), 1.0 microM OSU-HDAC42 was more biochemically potent (i.e., enzyme-inhibitory), as suggested by greater gene up-regulation and acetylation of both histone and nonhistone proteins. In p53-dysfunctional cells, however, OSU-HDAC42 was two- to eight-fold less inductive of p53-regulated genes, whereas also having a two-fold higher IC(50) than p53-functional cells, demonstrating some interaction with p53 tumor-suppressive cascades. These findings establish OSU-HDAC42 as a promising therapeutic agent for drug-resistant ovarian cancer and justify its further investigation.
组蛋白去乙酰化酶抑制剂（HDACIs）是一类抗肿瘤药物，此前已证明其对耐药癌细胞和小鼠异种移植瘤具有临床前化学增敏活性。然而，尽管临床研究已显示其对人类血液系统恶性肿瘤有效，但实体瘤试验结果却令人失望。我们之前研发了一种新型HDACI“OSU-HDAC42”，在此研究其对卵巢癌细胞系和异种移植瘤的活性。OSU-HDAC42，（i）与大多数HDACIs不同，在2.5微摩尔浓度时，可使G2期细胞增加超过五倍，随后出现G2期阻滞并伴有凋亡；（ii）在1.0微摩尔浓度时，可完全抑制细胞周期进展基因cdc2的信使核糖核酸表达；（iii）在低剂量（0.25 - 1.0微摩尔，作用24小时）时，可诱导肿瘤细胞上皮分化，形态学变化及上皮特异性细胞角蛋白上调超过五倍可证明这一点；（iv）能有效抑制多种卵巢癌细胞的生长，半数抑制浓度（IC50）值为0.5至1.0微摩尔，而对正常卵巢表面上皮细胞的毒性则低八倍（IC50为8.6微摩尔）；（v）可使铂耐药小鼠异种移植瘤对顺铂敏感。与临床批准的HDACI辛二酰苯胺异羟肟酸（伏立诺他）相比，1.0微摩尔的OSU-HDAC42在生化方面更具效力（即酶抑制作用更强），组蛋白和非组蛋白的基因上调及乙酰化程度更高可表明这一点。然而，在p53功能失调的细胞中，OSU-HDAC42对p53调控基因的诱导作用低两至八倍，其IC50也比p53功能正常的细胞高两倍，表明其与p53肿瘤抑制级联存在一定相互作用。这些发现表明OSU-HDAC42是一种有前景的耐药卵巢癌治疗药物，值得进一步研究。
