Unlocking Aspirin's Chemopreventive Activity: Role of Irreversibly Inhibiting Platelet Cyclooxygenase-1.
Unlocking Aspirin's Chemopreventive Activity: Role of Irreversibly Inhibiting Platelet Cyclooxygenase-1.
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DOI：
10.1158/1940-6207.capr-16-0241
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发表时间：
2017-02
期刊：
影响因子：
--
通讯作者：
Vijayan KV
中科院分区：
文献类型：
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作者：
Lichtenberger LM;Fang D;Bick RJ;Poindexter BJ;Phan T;Bergeron AL;Pradhan S;Dial EJ;Vijayan KV
阿司匹林消费与多种形式的癌症和转移性扩散到远处组织的发生率显着降低，导致癌症患者生存率增加的机制尚未得到充分理解。在这项研究中，以结肠癌为例，我们提供了体外（细胞培养）和体内（化学诱导的结肠癌小鼠模型）的证据，证明这种深刻的抗肿瘤作用可能与阿司匹林不可逆地抑制考克斯-1介导的血小板活化的能力有关，从而阻断血小板-癌细胞相互作用，促进癌细胞数量和侵袭潜力。该过程可能由血小板诱导的上皮-间充质转化（EMT）驱动，如使用共聚焦显微镜，基于细胞形态、生长特征和纤连蛋白表达的变化以及通过测量EMT标志物（波形蛋白、β-连环蛋白和SNAIL）表达变化的生化/分子分析所评估的。我们还提供了证据表明，一种新的，GI更安全的磷脂酰胆碱（PC）相关阿司匹林，PL 2200阿司匹林，具有相同或更显着的行动与未经修改的阿司匹林方面的抗血小板作用（体外-减少血小板活化，如通过测量培养基中血栓烷的释放和VEGF的释放所确定的;体内-抑制血小板数量/活化和外渗到肿瘤组织中）和化学预防（体外-抑制结肠细胞生长和侵袭活性;体内-抑制结肠发育不良、炎症和肿瘤块）。这些结果表明，阿司匹林的化学预防作用可能是由于，在某种程度上，药物阻断血小板的促肿瘤作用;和潜在的使用阿司匹林-PC/PL 2200作为一种有效的和更安全的化学预防剂的结直肠癌和可能的其他癌症。
The mechanism by which aspirin consumption is linked to significant reductions in the incidence of multiple forms of cancer and metastatic spread to distant tissues, resulting in increased cancer patient survival is not well understood. In this study, using colon cancer as an example, we provide both in vitro (cell culture) and in vivo (chemically-induced mouse model of colon cancer) evidence that this profound anti-neoplastic action may be associated with aspirin’s ability to irreversibly inhibit COX-1 mediated platelet activation, thereby blocking platelet-cancer cell interactions, which promote cancer cell number and invasive potential. This process may be driven by platelet-induced Epithelial-Mesenchymal Transition (EMT), as assessed using confocal microscopy, based upon changes in cell morphology, growth characteristics and fibronectin expression, and biochemical/molecular analysis by measuring changes in the expression of the EMT markers; vimentin, β-catenin, and SNAIL. We also provide evidence that a novel, GI-safer phosphatidylcholine (PC)-associated aspirin, PL2200 Aspirin, possesses the same or more pronounced actions vs unmodified aspirin with regard to antiplatelet effects (in vitro-reducing platelet activation as determined by measuring the release of thromboxane and VEGF release in culture medium; in vivo-inhibiting platelet number/activation and extravasation into tumor tissue) and chemoprevention (in vitro-inhibiting colonic cell growth, and invasive activity; in vivo-inhibiting colonic dysplasia, inflammation and tumor mass). These results suggest that aspirin’s chemopreventive effects may be due, in part, to the drug blocking the pro-neoplastic action of platelets; and the potential use of Aspirin-PC/PL2200 as an effective and safer chemopreventive agent for colorectal cancer and possibly other cancers.