Zebularine suppresses the apoptotic potential of 5-fluorouracil via cAMP/PKA/CREB pathway against human oral squamous cell carcinoma cells
Zebularine suppresses the apoptotic potential of 5-fluorouracil via cAMP/PKA/CREB pathway against human oral squamous cell carcinoma cells
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DOI：
10.1007/s00280-008-0833-4
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发表时间：
2009-07
影响因子：
3
通讯作者：
Maiko Suzuki;F. Shinohara;Manabu Endo;M. Sugazaki;S. Echigo;H. Rikiishi
中科院分区：
文献类型：
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作者：
Maiko Suzuki;F. Shinohara;Manabu Endo;M. Sugazaki;S. Echigo;H. Rikiishi
目的在口腔鳞癌（OSCC）的发生发展过程中，抑癌基因和肿瘤相关基因的启动子区DNA甲基化异常导致其表达沉默，这是口腔鳞癌细胞对5-氟尿嘧啶（5-FU）敏感性的重要决定因素之一。在这里，我们研究了表观遗传药物对5-FU cytotoxic. Methods的化疗效果，我们研究了DNA甲基转移酶（DNMT）抑制剂，zebularine（Zeb），对5-FU和顺铂（CDDP）的化疗敏感性的影响，通过MTT和TUNEL方法，并比较了分子作用机制与GSK 3 β抑制剂，LiCl，和Hsp 90抑制剂，结果在CDDP处理中发现Zeb或17-AAG组合的显著凋亡效应;然而，在与Zeb、17-AAG或LiCl孵育后观察到5-FU诱导的凋亡的相当大的抑制。Zeb的抑制作用与cAMP/PKA/CREB通路的激活有关，与17-AAG和LiCl的机制不同。抑制5-FU诱导的细胞凋亡与增加Bcl-2和Bcl-xL的表达依赖于转录因子CREB，并与胸苷酸synthes.ConclusionsIn本研究中的表达水平，我们确定了一个更详细的作用机制，其中Zeb抑制5-FU诱导的细胞凋亡。这些结果表明，由于DNMT抑制剂临床应用中的潜在有害作用，必须仔细研究联合治疗。
PurposeDuring tumorigenesis, tumor suppressor and tumor-related genes are commonly silenced by aberrant DNA methylation in their promoter regions, which is one of the important determinants of susceptibility to 5-fluorouracil (5-FU) in oral squamous cell carcinoma (OSCC) cells. Here, we examine the chemotherapeutic efficacy of epigenetic agents on 5-FU cytotoxicity.MethodWe investigated the effect of a DNA methyltransferase (DNMT) inhibitor, zebularine (Zeb), on the chemosensitivity of 5-FU and cisplatin (CDDP) by MTT and TUNEL methods, and compared the molecular mechanism of action with those of a GSK3β inhibitor, LiCl, and an Hsp90 inhibitor, 17-AAG.ResultsA significant apoptotic effect by a combination of Zeb or 17-AAG was found in CDDP treatment; however, considerable suppression of 5-FU-induced apoptosis was observed after incubation with Zeb, 17-AAG, or LiCl. Zeb’s suppressive effects were associated with activation of the cAMP/PKA/CREB pathway, differing from mechanisms of 17-AAG and LiCl. Suppression of 5-FU-induced apoptosis by Zeb was not associated with increased Bcl-2 and Bcl-xL expressions dependent on transcription factor CREB, and with the expression level of thymidylate synthase.ConclusionsIn the present study, we identified a more detailed mechanism of action by which Zeb suppresses 5-FU-induced apoptosis. These results indicate that combination therapies have to be carefully investigated due to potential harmful effects in the clinical application of DNMT inhibitors.