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首页> 外文期刊>Molecular cancer therapeutics >Antitumor activity of CTFB, a novel anticancer agent, is associated with the down-regulation of nuclear factor-kappaB expression and proteasome activation in head and neck squamous carcinoma cell lines.
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Antitumor activity of CTFB, a novel anticancer agent, is associated with the down-regulation of nuclear factor-kappaB expression and proteasome activation in head and neck squamous carcinoma cell lines.

机译：CTFB是一种新型抗癌药，其抗肿瘤活性与头颈部鳞状细胞癌细胞系中核因子-κB表达的下调和蛋白酶体的活化有关。

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摘要

This study aimed to characterize the antitumor activity of 5-Chloro-N-[2-[2-(4-chloro-phenyl)-3-methyl-butoxy]-5-trifluoromethyl-phenyl]-2-h ydroxy-benzamide (CTFB), a novel anticancer agent, in head and neck cancer cell lines, FaDu, SCC-25 and cisplatin-resistant CAL-27. CTFB was generated as a result of an extensive medicinal chemistry effort on a lead compound series discovered in a high-throughput screen for inducers of apoptosis. All cell lines showed significant growth delay in response to CTFB treatment at a concentration of 1 micromol/L with 17.16 +/- 2.08%, 10.92 +/- 1.22%, and 27.03 +/- 1.86% of cells surviving at 120 h in FaDu, CAL-27, and SCC-25, respectively. To define proteins involved in the mechanism of action of CTFB, we determined differences in the proteome profile of cell lines before and after treatment with CTFB using two-dimensional difference gel electrophoresis followed by computational image analysis and mass spectrometry. Eight proteins were found to be regulated by CTFB in all cell lines. All these proteins are involved in cytoskeleton formation and function and/or in cell cycle regulation. We showed that CTFB-induced cell growth delay was accompanied by cell cycle arrest at the G(0)-G(1) phase that was associated with the up-regulation of p21/WAF1 and p27/Kip1 expression and the down-regulation of cyclin D1. Furthermore, we showed that activity of CTFB depended on the down-regulation of nuclear factor-kappaB (NF-kappaB) and NF-kappaB p65 phosphorylated at Ser(536). The level of proteasome activity correlated with the response to CTFB treatment, and the down-regulation of NF-kappaB is accompanied by enhanced proteasome activity in all investigated head and neck cancer cell lines. In this report, we show that CTFB reveals multiple effects that lead to delayed cell growth. Our data suggest that this compound should be studied further in the treatment of head and neck cancer.
机译：这项研究旨在表征5-氯-N- [2- [2-（4-氯-苯基）-3-甲基-丁氧基] -5-三氟甲基-苯基] -2-h羟基苯甲酰胺的抗肿瘤活性（ CTFB）是一种新型抗癌药，可用于头颈部癌细胞系FaDu，SCC-25和顺铂耐药CAL-27。 CTFB是在对导致凋亡的高通量筛选中发现的先导化合物系列进行广泛药物化学努力后产生的。所有细胞系在浓度为1 micromol / L的CTFB处理下均显示出显着的生长延迟，其中FaDu在120 h存活的细胞有17.16 +/- 2.08％，10.92 +/- 1.22％和27.03 +/- 1.86％。 ，CAL-27和SCC-25。为了定义参与CTFB作用机制的蛋白质，我们使用二维差异凝胶电泳，然后通过计算图像分析和质谱分析，确定了CTFB处理前后细胞系蛋白质组谱的差异。发现八种蛋白质在所有细胞系中均受CTFB调控。所有这些蛋白质都参与细胞骨架的形成和功能和/或细胞周期调控。我们表明，CTFB诱导的细胞生长延迟伴随着细胞周期停滞在G（0）-G（1）期，这与p21 / WAF1和p27 / Kip1表达的上调以及P21 / WAF1表达的下调有关。细胞周期蛋白D1。此外，我们表明，CTFB的活性取决于在Ser（536）处磷酸化的核因子-kappaB（NF-kappaB）和NF-kappaB p65的下调。蛋白酶体活性水平与对CTFB治疗的反应相关，并且在所有研究的头颈癌细胞系中，NF-κB的下调都伴随着蛋白酶体活性的增强。在此报告中，我们表明CTFB揭示了导致细胞生长延迟的多种作用。我们的数据表明，该化合物应在头颈癌的治疗中进一步研究。

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