Current Status of Nonsteroidal Anti-inflammatory Drugs in Colorectal Cancer Prevention - Current Status of Nonsteroidal Anti-inflammatory Drugs in Colorectal Cancer Prevention - Open Access Pub

DOI10.14302/issn.2471-7061.jcrc-14-394 To date, lifestyle modification and screening are the main tools of the CRC preventive strategy. Chemoprevention, i.e. the use of specific agents (natural or chemical) with suggested antineoplastic effect, has been also proposed for the same purpose. Belonging to this category, NSAIDs have been widely investigated within the last two decades, with promising although not (yet) definitive results.1, 2, 3 These agents possibly act through the inhibition of the COX-1 and COX-2 enzymes - both involved in the conversion of arachidonic acid into prostaglandins, metabolites affecting inflammation and multiple potentially tumorigenic cellular processes (proliferation, apoptosis, angiogenesis etc).4, 5 The chemopreventive effect is exerted through retardment, regression or prevention of the development of adenomas (i.e. CRC precursors) resulting in the reduction in both number and size of existing lesions along with protection against new adenoma formation1, 2, 3, 5, 6, 7, 8, whereas antitumor effect has been also reported in established carcinomas.3, 7 Chemopreventive Mechanism Both COX-2 (albeit not COX-1) overexpression and PGE2 increase have been observed in colorectal tumors (polyps and cancers).4 Their carcinogenic role is probably mediated through several complex molecular pathways including -besides COX-2 induction- activation of oncogenes and cytokines and growth factor signaling, such as the Wnt (APC/b-catenin) and Ras pathways (both representing major tumorigenic steps).2, 3, 5 Nevertheless, COX-2 upregulation and the subsequent PGE2 accumulation results in the activation of particular genes with specific tumorigenic activities, such as cyclin-D proliferative factor, Bcl-2 anti-apoptotic oncogene and VEGF.3 Thus, the COX-derived PGE2 promotes tumor growth by increasing cell proliferation, migration and invasiveness, blocking apoptosis, impairing humoral and cellular immunity and inducing angiogenesis.3, 4, 5, 7 In this context the chemopreventive effect of NSAIDs is primarily attributed to their well known pharmacological activity to inhibit either COX-2 (selective inhibitors) or both COX-1 and COX-2 (conventional NSAIDs), resulting in suppression of prostaglandin synthesis. However, NSAID antineoplastic effect may be also exerted through COX independent mechanisms, including other specific drug targets such as NF-KB, caspases, PDEs, survinin, protein kinases etc.5, 7, 8, 10 Indirect effect on COX has been also reported specifically for aspirin (besides inhibitory action) through the anti-platelet activity of the