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 o
- PDF / 908,446 Bytes
- 27 Pages / 439.37 x 666.142 pts Page_size
- 18 Downloads / 197 Views
Abstract
Aspirin taken for several years at doses of at least 75 mg daily reduced longterm 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. COXindependent mechanisms of aspirin, such as the inhibition of NF-kB signaling and Wnt/b-catenin signaling and the acetylation of extra-COX proteins, have
M. Dovizio S. Tacconelli P. Patrignani (&) Center of Excellence on Aging (CeSI) and Department of Neuroscience and Imaging, G. d’Annunzio University, School of Medicine, Via dei Vestini 31, 66100 Chieti, Italy e-mail: [email protected] A. Bruno Center of Excellence on Aging (CeSI) and Department of Medicine and Aging, G. d’Annunzio University, School of Medicine, Via dei Vestini 31, 66100 Chieti, Italy
A. T. Chan and E. Detering (eds.), Prospects for Chemoprevention of Colorectal Neoplasia, Recent Results in Cancer Research 191, DOI: 10.1007/978-3-642-30331-9_3, Ó Springer-Verlag Berlin Heidelberg 2013
39
40
M. Dovizio et al.
been suggested to play a role in its chemopreventive effects. However, their relevance remains to be demonstrated in vivo at clinical doses. Abbreviations
15R-HETE 5-LOX ADP apaf-1 AA CRC COX EGFR ERK FAP FGF IGF IL LPS MPs mPGES-1 NK NSAID NF-kB PDGF PDGF PGI2 PG PKC Ser S1P Lef TX TIMP TCIPA TXAS VEGF
15R-hydroxyeicosapentaenoic acid 5-lipoxygenase Adenosine diphosphate Apoptotic protease activating factor-1 Arachidonic acid Colorectal cancer Cyclooxygenase Epidermal growth factor receptor Extracellular signal-regulated kinase Familial adenomatous polyposis Fibroblast growth factor Insulin-like growth factor Interleukin Bacterial endotoxin Microparticles Microsomal PGE2 synthase-1 Natural killer Nonsteroidal anti-inflammatory drug Nuclear factor kappa B Platelet-derived growth factor Platelet-derived growth factor Prostacyclin Prostaglandin Protein kinase C Serine Sphingosine-1-phosphate T-cell factor (Tcf)/lymphoid enhancer factor Thromboxane Tissue inhibitor of metalloproteinases Tumor cell-
Data Loading...
