Antimitogenic and chernosensitizing effects of the methylation inhibitor zebularine in ovarian cancer
Antimitogenic and chernosensitizing effects of the methylation inhibitor zebularine in ovarian cancer
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DOI：
10.1158/1535-7163.mct-05-0216
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发表时间：
2005-10-01
影响因子：
5.7
通讯作者：
Nephew, KP
中科院分区：
文献类型：
--
作者：
Balch, C;Yan, P;Nephew, KP
肿瘤抑制基因 CpG 岛内的脱氧胞嘧啶甲基化在耐药性卵巢癌的发生和进展中发挥着重要作用。因此，针对肿瘤抑制因子去甲基化/重新表达的表观遗传疗法可能会逆转恶性表型并使顽固性肿瘤变得化疗敏感。在本报告中，我们检查了去甲基化剂zebularine [1-(β-D-呋喃核糖基)-1,2-二氢嘧啶-2-酮]与著名的甲基化抑制剂5-aza-2-脱氧胞苷(5-aza-dC)相比，其抑制卵巢癌细胞增殖以及去甲基化和诱导肿瘤抑制因子的能力 基因。 Zebularine 对卵巢癌细胞系 Hey、A2780 和顺铂耐药 A2780/CP 具有显着的 (> 5aza-dC) 抗增殖作用，且呈剂量依赖性（zebularine 与 5-aza-dC 相比，48 小时抑制率为 65% 与 35%）。此外，0.2 mmol/L zebularine 处理 48 小时显着诱导肿瘤抑制因子 ras 相关结构域家族 1A 和人 MutL 同源物 1 的去甲基化。还观察到 RASSF1A 基因重新表达，以及其他两种肿瘤抑制因子 ARHI 和 BLU 的重新表达，尽管水平与 5-aza-dC 诱导的水平不同。 DNA 甲基化的整体分析显示，通过甲基接受测定确定，5-aza-dC 和 zebularine 具有相似的整体去甲基化（2.5 至 3 倍）。然而，通过差异甲基化杂交测定，观察到各个基因座去甲基化的差异。最后，我们发现 zebularine 可以使耐药细胞系 A2780/CP 对顺铂重新敏感，使传统药物的 IC50 降低 16 倍。总之，zebularine 似乎是一种有前途的临床候选药物，可以单独使用或与常规疗法联合使用，用于治疗耐药性卵巢癌。
Deoxycytosine methylation within CpG islands of tumor suppressor genes plays a prominent role in the development and progression of drug-resistant ovarian cancer. Consequently, epigenetic therapies directed toward tumor suppressor demethylation/reexpression could potentially reverse malignant phenotypes and chemosensitize recalcitrant tumors. In this report, we examined the demethylating agent zebularine [1-(beta-D-ribofuranosyl)-1,2-dihydropyrimidin-2-one], in comparison with the well-known methylation inhibitor 5-aza-2 -deoxycytidine (5-aza-dC), for its ability to inhibit ovarian cancer cell proliferation and to demethylate and induce tumor suppressor genes. Zebularine exerted significant (> 5aza-dC) antiproliferative effects against the ovarian cancer cell lines Hey, A2780, and the cisplatin-resistant A2780/CP in a dose-dependent manner (65% versus 35% inhibition at 48 hours, zebularine versus 5-aza-dC). Moreover, 48-hour treatment with 0.2 mmol/L zebularine significantly induced demethylation of the tumor suppressors ras-associated domain family 1A and human MutL homologue-1. RASSF1A gene reexpression was also observed, as was reexpression of two other tumor suppressors, ARHI and BLU, although levels differed from those induced by 5-aza-dC. Global analyses of DNA methylation revealed similar overall demethylation (2.5- to 3-fold) by 5-aza-dC and zebularine as determined by methyl acceptance assay. However, differences in demethylation of individual loci were observed as determined by differential methylation hybridization. Finally, we found that zebularine could resensitize the drug-resistant cell line A2780/CP to cisplatin, with a 16-fold reduction in the IC50 of that conventional agent. In summary, zebularine seems to be a promising clinical candidate, singly or combined with conventional regimens, for the therapy of drug-resistant ovarian cancer.