Epigenetic regulation of chemosensitivity to 5-fluorouracil and cisplatin by zebularine in oral squamous cell carcinoma.
Epigenetic regulation of chemosensitivity to 5-fluorouracil and cisplatin by zebularine in oral squamous cell carcinoma.
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DOI：
10.3892/ijo.31.6.1449
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发表时间：
2007-12
影响因子：
5.2
通讯作者：
Maiko Suzuki;F. Shinohara;K. Nishimura;S. Echigo;H. Rikiishi
中科院分区：
文献类型：
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作者：
Maiko Suzuki;F. Shinohara;K. Nishimura;S. Echigo;H. Rikiishi
表观遗传学改变如组蛋白乙酰化和DNA甲基化在调节细胞周期和细胞凋亡的基因表达中起重要作用，可能影响癌症的化学敏感性。以前，我们已经报道了辛二酰苯胺异羟肟酸（SAHA），一种新开发的组蛋白去乙酰化酶抑制剂，与顺铂（CDDP）的组合对人口腔鳞状细胞癌（OSCC）细胞系HSC-3具有协同细胞毒性。在这项研究中，我们使用了一种新的DNA甲基转移酶抑制剂，zebularine（Zeb），调查的表观遗传影响的敏感性癌细胞株5-氟尿嘧啶（5-FU）或顺铂通过评估凋亡诱导。CDDP或5-FU单独或与Zeb或SAHA联合治疗持续48或72小时。在HSC-3细胞中，Zeb对CDDP具有化疗敏感性，但对5-FU没有，而SAHA对CDDP和5-FU均显示出疗效。我们发现Zeb对HSC-3细胞具有强的抗增殖活性，表现为细胞生长和G2/M细胞周期阶段积累的减少。此外，DNA甲基化可能是二氢嘧啶脱氢酶（DPD）的调节机制，已知DPD是5-FU耐药的主要因素。DPD抑制剂CDHP（5-chloro-2，4-dihydroxypyridine）对5-FU单独或联合应用有增强作用。总之，本研究表明，低剂量（IC 20）的Zeb可以敏化癌细胞对CDDP，这可能是一个重要的特点，为实体肿瘤治疗，DPD和其他代理人激活的Zeb在癌细胞中可能是一个抑制因子在5-FU诱导的细胞凋亡的反应。
Epigenetic alterations such as histone acetylation and DNA methylation play an important role in the regulation of gene expression for cell cycles and apoptosis that may affect the chemosensitivity of cancers. Previously, we have reported that the combination of suberoylanilide hydroxamic acid (SAHA), a newly developed histone deacetylase inhibitor, with cisplatin (CDDP) possessed synergistic cytotoxicity against human oral squamous cell carcinoma (OSCC) cell line HSC-3. In this study, we used a novel DNA methyltransferase inhibitor, zebularine (Zeb), to investigate the epigenetic influence on the sensitivity of carcinoma cell lines to 5-fluorouracil (5-FU) or CDDP by evaluating apoptotic inducibility. Treatment with CDDP or 5-FU either alone or in combination with Zeb or SAHA continued for 48 or 72 h. In HSC-3 cells, Zeb had chemosensitive efficacy with CDDP, but not 5-FU, whereas SAHA showed efficacy with both CDDP and 5-FU. We showed that Zeb has strong anti-proliferative activity against HSC-3 cells, shown by decreased cellular growth and G2/M cell cycle phase accumulation. Furthermore, DNA methylation could be a regulatory mechanism for dihydropyrimidine dehydrogenase (DPD), known to be a principal factor in 5-FU resistance. CDHP (5-chloro-2,4-dihydroxypyridine), an inhibitor of DPD, had an enhancing effect on the apoptotic ability of 5-FU alone or 5-FU/Zeb combination. In conclusion, the present study suggests that low-dose (IC20) Zeb may sensitize cancer cells to CDDP, which may be an important characteristic for solid cancer treatment, and that DPD and other agents activated by Zeb in cancer cells could be an inhibitory factor in the response to apoptosis induced by 5-FU.