阿司匹林和塞来昔布靶向哺乳动物神经氨酸酶-1阻碍表皮生长因子受体信号轴并诱导胰腺癌细胞凋亡的新分子机制。

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郭丽丽，王志强，王志强

阿司匹林和塞来昔布靶向哺乳动物神经氨酸酶-1阻碍表皮生长因子受体信号轴并诱导胰腺癌细胞凋亡的新分子机制。

中国医药杂志。2020年10月8日;14:4149-4167。doi: 10.2147 / DDDT.S264122。eCollection 2020。

PubMed ID

33116404 (PubMed视图

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摘要

背景:阿司匹林(乙酰水杨酸)和塞来昔布已被用作潜在的抗癌疗法。阿司匹林在环加氧酶(COX)依赖和不依赖通路上发挥其治疗作用，以减少肿瘤生长和抑制肿瘤发生。塞来昔布是一种选择性环氧合酶-2 (COX-2)抑制剂，可减少引起炎症和疼痛的因素。问题是阿司匹林和塞来昔布是否有其他具有同等或更高治疗效果的分子靶标，具有显著的抗癌预防益处。目的:在此，我们提出阿司匹林和塞来昔布通过靶向和抑制哺乳动物神经氨酸酶-1 (nau -1)发挥抗癌作用。据报道，nue -1可调节几种受体酪氨酸激酶(rtk)和toll样受体及其下游信号通路的激活。据报道，nau -1与基质金属蛋白酶-9 (MMP-9)和G蛋白偶联受体(GPCRs)的复合物在外畴与rtk相连。材料与方法:采用WST-1细胞活力测定法、Caspase 3/7测定法和Annexin V测定法评价miapca -2、PANC-1和耐吉西他滨PANC-1变异(PANC-1 GemR)细胞处理后的细胞活力并检测凋亡和坏死细胞。显微成像、凝集素细胞化学和流式细胞术检测α -2,3唾液酸水平。采用表皮生长因子(EGF)刺激的活细胞唾液酸酶测定法和神经氨酸酶测定法检测Neu-1活性。 Immunocytochemistry was used to detect levels of EGFR and phosphorylated EGFR (pEGFR) following treatment. Results: For the first time, aspirin and celecoxib were shown to significantly inhibit Neu-1 sialidase activity in a dose- and time-dependent manner following stimulation with EGF. Aspirin blocked Neu-1 desialylation of alpha-2,3-sialic acid expression following 30 min stimulation with EGF. Aspirin and celecoxib significantly and dose-dependently inhibited isolated neuraminidase (Clostridium perfringens) activity on fluorogenic substrate 2'-(4-methylumbelliferyl)-alpha-D-N-acetylneuraminic acid (4-MUNANA). Aspirin inhibited phosphorylation of the EGFR in EGF-stimulated cells. Aspirin dose- and time-dependently induced CellEvent caspase-3/7(+) cells as well as apoptosis and necrosis on PANC-1 cells. Conclusion: These findings signify a novel multimodality mechanism(s) of action for aspirin and celecoxib, specifically targeting and inhibiting Neu-1 activity, regulating EGF-induced growth receptor activation and inducing apoptosis and necrosis in a dose- and time-dependent manner. Repurposing aspirin and celecoxib as anti-cancer agents may also upend other critical targets involved in multistage tumorigenesis regulated by mammalian neuraminidase-1. Significance: These findings may be the missing link connecting the anti-cancer efficacy of NSAIDs to the role of glycosylation in inflammation and tumorigenesis.

引用本文的药物库数据

药物靶点

药物	目标	种类	生物	药理作用	行动
乙酰水杨酸	Sialidase-1	蛋白质	人类	未知的	抑制剂	细节
塞来昔布	Sialidase-1	蛋白质	人类	是的	抑制剂	细节

药物酶

药物	酶	种类	生物	药理作用	行动
塞来昔布	前列腺素G/H合成酶2	蛋白质	人类	未知的	抑制剂	细节