PDF(Pubmed)
Abstract：
Cyclooxygenase 2 (COX-2) and 5-lipoxygenase (5-LOX) are overexpressed in gastric cancer cells, the dual inhibitors of which exhibit potential against metastasis and invasion with fewer side effects. To discover inhibitors targeting COX-2 and 5-LOX, we conducted ultrafiltration and enrichment calculation to screen candidates in quaternary alkaloids (QAs) from Zanthoxylum simulans through LC and LC-Q-TOF. For intensive peaks, peaks 19 (berberine) and 21 (chelerythrine) were observed as the most potent dual candidates and showed selective affinity to 5-LOX over COX-2. Peak 19 showed an enrichment at 4.36 for COX-2 and 22.81 for 5-LOX, while peak 21 showed an enrichment at 7.81 for COX-2 and 24.49 for 5-LOX. Molecular docking results revealed chelerythrine as a better dual inhibitor, showing time- and dose-dependent anti-proliferation against AGS cells. Bio-informatics strategies, such as Gene Expression Omnibus (GEO), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG), suggested that hormone pathways in gastric cancer cells might be mediated by chelerythrine. Further reviews and summaries helped outline the mechanisms by which COX-2/5-LOX inhibitors might promote apoptosis in gastric cancer cells via estrogen, thyroid, and oxytocin signaling pathways. Chelerythrine was also added to gastric cancer cells to verify the regulation of these three signaling pathways. As a result, significant calling back of thyroid-stimulating hormone receptor (TSHR), thyroid hormone α3 (TRα3), and thyroid hormone receptor β1 (TRβ1) and suppressing estrogen receptor α36 (ER-α36)-Src could benefit the anti-proliferation of chelerythrine. However, it was disappointing that regulation of estrogen receptor α66 (ER-α66), estrogen receptor β (ER-β), and oxytocin receptor (OTR) contributed inversely negative effects on anti-gastric cancer cells. At present, the integrative study not only revealed chelerythrine as the most potent dual COX-2/5-LOX inhibitor from QAs but also generally highlighted that comprehensive regulation of the estrogen, thyroid, and oxytocin pathway should be noted once gastric cancer cells were treated with inflammatory inhibitors.
摘要：
环氧合酶2（COX-2）和5-脂氧合酶（5-LOX）在胃癌细胞中过度表达，其双重抑制剂表现出抗转移和侵袭的潜力，副作用较少。为了发现靶向COX-2和5-LOX的抑制剂，我们进行了超滤和富集计算，以通过LC和LC-Q-TOF从花椒中筛选出四元生物碱（QAs）候选物。对于密集高峰，峰19（小檗碱）和21（白屈菜红碱）被观察为最有效的双重候选物，并且显示出对5-LOX的选择性亲和力超过COX-2。峰19显示COX-2的富集为4.36，5-LOX的富集为22.81，而峰21显示COX-2的富集为7.81，5-LOX的富集为24.49。分子对接结果显示白屈菜红碱是更好的双重抑制剂，显示针对AGS细胞的时间和剂量依赖性抗增殖。生物信息学策略，如基因表达综合(GEO)，基因本体论（GO），和京都基因和基因组百科全书（KEGG），提示胃癌细胞中的激素途径可能是由白屈菜红碱介导的。进一步的综述和总结有助于概述COX-2/5-LOX抑制剂可能通过雌激素促进胃癌细胞凋亡的机制。甲状腺，和催产素信号通路。还将白屈菜红碱添加到胃癌细胞中以验证这三个信号通路的调节。因此,促甲状腺激素受体（TSHR）的显著回调，甲状腺激素α3（TRα3），甲状腺激素受体β1（TRβ1）和抑制雌激素受体α36（ER-α36）-Src可能有利于白屈菜红碱的抗增殖。然而,令人失望的是调节雌激素受体α66（ER-α66），雌激素受体β（ER-β），和催产素受体（OTR）对抗胃癌细胞具有相反的负面影响。目前,这项综合研究不仅揭示了白屈菜红碱是QAs中最有效的双重COX-2/5-LOX抑制剂，而且还普遍强调了雌激素的综合调节，甲状腺，和催产素途径应注意，一旦胃癌细胞用炎症抑制剂治疗。
