Abstract
Epidemiological and clinical studies suggest that non-steroidal anti-inflammatory drugs (NSAIDs), including cyclooxygenase (COX)-2 selective inhibitors, reduce the risk of developing cancer. Experimental studies in human cancer cell lines and rodent models of carcinogenesis support these observations by providing strong evidence for the antineoplastic properties of NSAIDs. The involvement of COX-2 in tumorigenesis and its overexpression in various cancer tissues suggest that inhibition of COX-2 is responsible for the chemopreventive efficacy of these agents. However, the precise mechanisms by which NSAIDs exert their antiproliferative effects are still a matter of debate. Numerous other studies have shown that NSAIDs can act through COX-independent mechanisms. This review provides a detailed description of the major COX-independent molecular targets of NSAIDs and discusses how these targets may be involved in their anticancer effects. Toxicities resulting from COX inhibition and the suppression of prostaglandin synthesis preclude the long-term use of NSAIDs for cancer chemoprevention. Furthermore, chemopreventive efficacy is incomplete and treatment often leads to the development of resistance. Identification of alternative NSAID targets and elucidation of the biochemical processes by which they inhibit tumor growth could lead to the development of safer and more efficacious drugs for cancer chemoprevention.
Highlights
Non-steroidal anti-inflammatory drugs (NSAIDs) are a diverse class of drugs commonly used for the treatment of inflammatory conditions, analgesia, and fever
These results indicate that inhibition of cGMP PDEs by NSAIDs have the potential to restore APC tumor-suppressor function in colorectal, breast, and potentially other cancer types by attenuating oncogenic Wnt signaling, thereby leading to apoptosis induction
Overexpression of PPARδ can prevent the reduction in 14-3-3ε levels and confer apoptosis resistance, while overexpression of 14-3-3ε alone was found to be sufficient to significantly reduce apoptosis levels after NSAID treatment. These findings demonstrate the importance of PPARδ and 14-3-3ε as effectors of NSAID-mediated apoptosis and validate their potential as novel targets for cancer prevention and therapy
Summary
Non-steroidal anti-inflammatory drugs (NSAIDs) are a diverse class of drugs commonly used for the treatment of inflammatory conditions, analgesia, and fever. The concentration of a given NSAID or selective COX-2 inhibitor required to inhibit tumor cell proliferation in vitro is much higher than that required to inhibit COX-1 and/or COX-2 activity [37] This is an important consideration since experimental studies in rodent models, as well as clinical studies typically demonstrate chemopreventive efficacy of NSAIDs only at doses higher than those necessary for anti-inflammatory effects. It has to be noted, that prostaglandin levels are decreased in the colorectal mucosa of FAP patients with adenoma regression on sulindac [41, 42] These results may explain the modest chemopreventive efficacy of currently available NSAIDs such as sulindac or celecoxib at the anti-inflammatory dosages and highlight the need for more potent and selective inhibitors. Exisulind did not receive FDA approval because of hepatotoxicity, which limited the dosage
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