Antiproliferative and proapoptotic effects of histone deacetylase inhibitors on gastrointestinal neuroendocrine tumor cells
Antiproliferative and proapoptotic effects of histone deacetylase inhibitors on gastrointestinal neuroendocrine tumor cells
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DOI：
10.1677/erc.1.01249
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发表时间：
2006-12-01
影响因子：
3.9
通讯作者：
Scheruebl, Hans
中科院分区：
文献类型：
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作者：
Baradari, Viola;Huether, Alexander;Scheruebl, Hans
晚期神经内分泌肿瘤（NETS）的治疗方案并不令人满意。因此，迫切需要创新的治疗方法。组蛋白脱乙酰酶 (HDAC) 的抑制是一种有前途的癌症治疗新方法。虽然多种 HDAC 抑制剂已进入临床试验，但 HDAC 抑制对 NET 的影响尚未得到研究。因此，我们评估了三种不同的 HDAC 抑制剂曲古抑菌素 A (TSA)、丁酸钠 (NaB) 和 MS-275 对胃肠道 NET 细胞系 CM 和 BON 生长和凋亡的抗肿瘤作用。我们可以证明 HDAC 抑制剂量依赖性地抑制两种细胞系的增殖，IC50 值从毫摩尔 (NaB) 到微摩尔 (MS-275) 和纳摩尔范围 (TSA)。此外，HDAC 抑制可有效诱导细胞凋亡，并伴有 DNA 断裂、高达 12 倍的 caspase-3 激活和小丑调节的 Bcl-2 表达。此外，HDAC 抑制导致细胞周期停滞在 G(1)-S-转变，这与细胞周期蛋白 D1 表达的抑制以及 p21 和 p27 表达的诱导有关。对于 BON 细胞，我们观察到 G(2)/M 期出现额外的阻断，这与细胞周期蛋白 B1 的下调相关。此外，还评估了 MS-275 和生长抑素或合成生长抑素类似物奥曲肽的联合治疗。生长抑素及其稳定类似物奥曲肽均未增强 MS-275 在 NET 细胞中的抗增殖作用。总之，我们的数据表明 HDAC 抑制是治疗 NET 疾病的一种有前途的新方法，应在临床研究中进行评估。
Treatment options of advanced neuroendocrine tumors (NETS) are unsatisfactory. Hence, innovative therapeutic approaches are urgently needed. Inhibition of histone deacetylases (HDACs) is a promising new approach in cancer therapy. While several HDAC inhibitors have already entered clinical trials, the effect of HDAC inhibition on NET has not been investigated. Therefore, we evaluated the antineoplastic effects of three different HDAC inhibitors, trichostatin A (TSA), sodium butyrate (NaB), and MS-275, on growth and apoptosis of the gastrointestinal NET cell lines CM and BON. We could demonstrate that HDAC inhibition dose-dependently inhibited proliferation of both cell lines with IC50 values varying from the millimolar (NaB) to the micromolar (MS-275) and the nanomolar range (TSA). Moreover, HDAC inhibition potently induced apoptosis, which was accompanied by DNA-fragmentation, an up to 12-fold caspase-3 activation and clownregulated Bcl-2 expression. Furthermore, HDAC inhibition resulted in cell cycle arrest at the G(1)-S-transition, which was associated with the suppression of cyclin D1 expression and induction of p21 and p27 expression. For BON cells, we observed an additional block in the G(2)/M phase, which was aligned with a downregulation of cyclin B1. In addition, combined treatment with MS-275 and somatostatin or the synthetic somatostatin analog octreotide was evaluated. Neither somatostatin nor its stable analog octreotide augmented the antiproliferative effect of MS-275 in NET cells. To conclude, our data show that HDAC inhibition is a promising new approach in the treatment of NET disease, which should be evaluated in clinical studies.