A plentiful literature has linked colorectal cancer (CRC) to inflammation and prostaglandin-endoperoxide synthase (PTGS)2 expression. Accordingly, several nonsteroidal antiinflammatory drugs (NSAIDs) have been tested often successfully in CRC chemoprevention despite their different ability to specifically target PTGS2 and the low or null expression of PTGS2 in early colon adenomas. Some observational studies showed an increased survival for patients with CRC assuming NSAIDs after diagnosis, but no clinical trial has yet demonstrated the efficacy of NSAIDs against established CRC, where PTGS2 is expressed at high levels. The major limits for the application of NSAIDs, or specific PTGS2 inhibitors, as adjuvant drugs in CRC are (1) a frequent confusion about the physiological role of PTGS1 and PTGS2, reflecting in CRC pathology and therapy; (2) the presence of unavoidable side effects linked to the intrinsic function of these enzymes; (3) the need of established criteria and markers for patient selection; and (4) the evaluation of the immunomodulatory potential of PTGS2 inhibitors as possible adjuvants for immunotherapy. This review has been written to rediscover the multifaceted potential of PTGS2 targeting, hoping it could act as a starting point for a new and more aware application of NSAIDs against CRC.
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