Dovizio Melania, Bruno Annalisa, Tacconelli Stefania, Patrignani Paola
Department of Neuroscience and Imaging, G. d'Annunzio University, School of Medicine, Via dei Vestini 31, Chieti, Italy.
Recent Results Cancer Res. 2013;191:39-65. doi: 10.1007/978-3-642-30331-9_3.
Aspirin taken for several years at doses of at least 75 mg daily reduced long-term incidence and mortality due to colorectal cancer. The finding of aspirin benefit at low-doses given once daily, used for cardioprevention, locates the antiplatelet effect of aspirin at the center of its antitumor efficacy. In fact, at low-doses, aspirin acts mainly by an irreversible inactivation of platelet cyclooxygenase (COX)-1 in the presystemic circulation, which translates into a long-lasting inhibition of platelet function. Given the short half-life of aspirin in the human circulation(approximately 20 min) and the capacity of nucleated cells to resynthesize the acetylated COX-isozyme(s), it seems unlikely that a nucleated cell could be the target of aspirin chemoprevention. These findings convincingly suggest that colorectal cancer and atherothrombosis may share a common mechanism of disease, i.e. platelet activation in response to epithelial(in tumorigenesis) and endothelial(in tumorigenesis and atherothrombosis) injury. Activated platelets may also enhance the metastatic potential of cancer cells (through a direct interaction and/or the release of soluble mediators or exosomes) at least in part by inducing the overexpression of COX-2. COX-independent mechanisms of aspirin, such as the inhibition of NF-kB signaling and Wnt/β-catenin signaling and the acetylation of extra-COX proteins, have been suggested to play a role in its chemopreventive effects. However, their relevance remains to be demonstrated in vivo at clinical doses.
每天服用至少75毫克阿司匹林数年可降低结直肠癌的长期发病率和死亡率。在用于心脏预防的每日一次低剂量阿司匹林中发现的益处，将阿司匹林的抗血小板作用定位为其抗肿瘤功效的核心。事实上，在低剂量下，阿司匹林主要通过在体循环前不可逆地使血小板环氧化酶（COX）-1失活，从而转化为对血小板功能的持久抑制。鉴于阿司匹林在人体循环中的半衰期较短（约20分钟）以及有核细胞重新合成乙酰化COX同工酶的能力，有核细胞似乎不太可能成为阿司匹林化学预防的靶点。这些发现令人信服地表明，结直肠癌和动脉粥样硬化血栓形成可能共享一种共同的疾病机制，即响应上皮（在肿瘤发生中）和内皮（在肿瘤发生和动脉粥样硬化血栓形成中）损伤而发生的血小板活化。活化的血小板还可能至少部分地通过诱导COX-2的过表达来增强癌细胞的转移潜能（通过直接相互作用和/或可溶性介质或外泌体的释放）。阿司匹林的COX非依赖性机制，如抑制NF-κB信号传导和Wnt/β-连环蛋白信号传导以及COX外蛋白质的乙酰化，已被认为在其化学预防作用中发挥作用。然而，它们的相关性仍有待在临床剂量下在体内得到证实。
