Mode of action of aspirin as a chemopreventive agent.
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.
Department of Neuroscience and Imaging, G. d'Annunzio University, School of Medicine, Via dei Vestini 31, Chieti, Italy.
Melania
M
Dovizio
Annalisa
A
Bruno
Stefania
S
Tacconelli
Paola
P
Patrignani
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D001241:Aspirin / Q000493:pharmacokinetics / Q000494:pharmacology*; D001792:Blood Platelets / Q000502:physiology; D015179:Colorectal Neoplasms / Q000517:prevention & control*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D006801:Humans; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology
D016588:Anticarcinogenic Agents; D016861:Cyclooxygenase Inhibitors; D011451:Prostaglandin-Endoperoxide Synthases; D001241:Aspirin