Identification of aspirin analogues that repress NF-κB signalling and demonstrate anti-proliferative activity towards colorectal cancer in vitro and in vivo
Identification of aspirin analogues that repress NF-κB signalling and demonstrate anti-proliferative activity towards colorectal cancer in vitro and in vivo
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DOI：
10.3892/or.2014.3373
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发表时间：
2014-10-01
期刊：
影响因子：
4.2
通讯作者：
Nicholl, Iain D.
中科院分区：
文献类型：
--
作者：
Claudius, Ann-Katrin;Kankipati, Chandra S.;Nicholl, Iain D.
大量证据表明，阿司匹林和相关的非甾体抗炎药（NSAID）具有潜在的化学预防/治疗药物。然而，由于这些药物的潜在副作用，不能普遍推荐用于预防目的。在这里，我们比较了阿司匹林的生长抑制和机械活性的两种新的类似物，二阿司匹林（DiA）和富马酰二阿司匹林（F-DiA）。我们发现，阿司匹林类似物抑制细胞增殖和诱导结直肠癌细胞凋亡的剂量明显低于阿司匹林。与阿司匹林类似，我们发现对类似物的早期反应是细胞周期蛋白D1水平的降低和NF-κ B通路的刺激。这种刺激与NF-κ B转录活性基础水平的显著降低相关，与阿司匹林的先前数据一致。然而，与阿司匹林相反，DiA和F-DiA活性与RelA的核仁积累无关。对于所有试验，F-DiA比DiA具有更快速和更显著的效果，确定该药剂对结肠直肠癌特别有效。在小鼠中使用同基因结直肠肿瘤模型，我们发现，虽然两种药物在体内均显着抑制肿瘤生长，但这种作用对F-DiA尤其明显。这些数据鉴定了两种在体外和体内对结肠直肠癌有活性的化合物。他们还确定了这些药物的潜在作用机制，并阐明了可能对阿司匹林的抗肿瘤作用很重要的化学结构。
Substantial evidence indicates that aspirin and related non-steroidal anti-inflammatory drugs (NSAIDs) have potential as chemopreventative/therapeutic agents. However, these agents cannot be universally recommended for prevention purposes due to their potential side-effect profiles. Here, we compared the growth inhibitory and mechanistic activity of aspirin to two novel analogues, diaspirin (DiA) and fumaryl diaspirin (F-DiA). We found that the aspirin analogues inhibited cell proliferation and induced apoptosis of colorectal cancer cells at significantly lower doses than aspirin. Similar to aspirin, we found that an early response to the analogues was a reduction in levels of cyclin D1 and stimulation of the NF-kappa B pathway. This stimulation was associated with a significant reduction in basal levels of NF-kappa B transcriptional activity, in keeping with previous data for aspirin. However, in contrast to aspirin, DiA and F-DiA activity was not associated with nucleolar accumulation of RelA. For all assays, F-DiA had a more rapid and significant effect than DiA, identifying this agent as particularly active against colorectal cancer. Using a syngeneic colorectal tumour model in mice, we found that, while both agents significantly inhibited tumour growth in vivo, this effect was particularly pronounced for F-DiA. These data identify two compounds that are active against colorectal cancer in vitro and in vivo. They also identify a potential mechanism of action of these agents and shed light on the chemical structures that may be important for the antitumour effects of aspirin.