Flurbiprofen benzyl nitrate (NBS-242) inhibits the growth of A-431 human epidermoid carcinoma cells and targets β-catenin.
Flurbiprofen benzyl nitrate (NBS-242) inhibits the growth of A-431 human epidermoid carcinoma cells and targets β-catenin.
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DOI：
10.2147/dddt.s43771
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发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Kashfi K
中科院分区：
文献类型：
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作者：
Nath N;Liu X;Jacobs L;Kashfi K
Wnt/β-catenin/T细胞因子（TCF）信号通路在非黑色素瘤皮肤癌（NMSC）的发生发展中起重要作用。释放一氧化氮的非甾体抗炎药（NO-NSAID）是一种化学预防剂，由传统的NSAID通过化学间隔物连接到NO释放部分组成。以前，我们表明，芳香族间隔增强了一个特定的NO-NSAID的效力相比，脂肪族间隔。我们合成了一种释放NO的NSAID与芳香族间隔基（氟比洛芬苄基硝酸酯，NBS-242），并使用人皮肤癌细胞系A-431，我们评估了其对细胞动力学，Wnt/β-连环蛋白，细胞周期蛋白D1和半胱天冬酶-3的影响。NBS-242抑制A-431癌细胞生长的效力是氟比洛芬的约15倍，是具有脂肪族间隔基的NO-氟比洛芬的5倍，NBS-242、NO-氟比洛芬和氟比洛芬的生长抑制半数最大抑制浓度（IC 50）分别为60 ± 4 μM、320 ± 20 μM和880 ± 65 μM。这种作用与增殖抑制、细胞在细胞周期的G 0/G1期的积累以及凋亡细胞群的增加有关。NBS-242可在A-431细胞的胞浆和胞核中切割β-catenin。NBS-242激活半胱天冬酶-3，其激活反映在半胱天冬酶原-3的切割中。为了测试β-连环蛋白切割的功能后果，我们测定了Wnt反应基因cyclin D1的表达。NBS-242以浓度依赖性方式降低细胞周期蛋白D1水平。这些发现确立了NBS-242在A-431人表皮样癌细胞中的强抑制作用。NBS-242调节在确定细胞质量中重要的参数。
The Wnt/β-catenin/T cell factor (TCF) signaling pathway is important in the development of nonmelanoma skin cancers (NMSCs). Nitric-oxide-releasing nonsteroidal anti-inflammatory drugs (NO-NSAIDs) are chemopreventive agents consisting of a traditional NSAID attached to an NO-releasing moiety through a chemical spacer. Previously we showed that an aromatic spacer enhanced the potency of a particular NO-NSAID compared to an aliphatic spacer. We synthesized an NO-releasing NSAID with an aromatic spacer (flurbiprofen benzyl nitrate, NBS-242), and using the human skin cancer cell line A-431, we evaluated its effects on cell kinetics, Wnt/β-catenin, cyclin D1, and caspase-3. NBS-242 inhibited the growth of A-431 cancer cells, being ~15-fold more potent than flurbiprofen and up to 5-fold more potent than NO-flurbiprofen with an aliphatic spacer, the half maximal inhibitory concentrations (IC50) for growth inhibition being 60 ± 4 μM, 320 ± 20 μM, and 880 ± 65 μM for NBS-242, NO-flurbiprofen, and flurbiprofen, respectively. This effect was associated with inhibition of proliferation, accumulation of cells in the G0/G1 phase of the cell cycle, and an increase in apoptotic cell population. NBS-242 cleaved β-catenin both in the cytoplasm and the nucleus of A-431 cells. NBS-242 activated caspase-3 whose activation was reflected in the cleavage of procaspase-3. To test the functional consequence of β-catenin cleavage, we determined the expression of cyclin D1, a Wnt-response gene. NBS-242 reduced cyclin D1 levels in a concentration dependent manner. These findings establish a strong inhibitory effect of NBS-242 in A-431 human epidermoid carcinoma cells. NBS-242 modulates parameters that are important in determining cellular mass.