Endocrine Abstracts

The antitumor properties of non-steroidal anti-inflammatory drugs (NSAIDs), with respect to both cancer prevention and therapy, have raised considerable interest in the last two decades, leading to well consolidated evidences in gastrointestinal cancers, especially colorectal cancer. NSAID action has been proposed to occur through two independent modes: a COX-dependent one, mainly involving the inhibition of COX-2-mediated PGE2 production, and a COX-independent one, mainly involving direct toxicity to tumor cells. Among NSAIDs, Celecoxib is considered particularly promising as antitumor drug because of both selective COX-2 inhibition and powerful COX-independent toxicity on tumor cells.

However, I have recently demonstrated that the direct toxicity of Celecoxib, mostly observed in vitro, relies on precipitate-dependent cell damage rather than molecular effects (Sacchetti, J Cell Biochem. 2013 Jun; 114(6): 1434–44) and requires concentrations of the drug much higher than those observed during therapy, with the exception of some regions of the gastrointestinal tract. If, in the latter, COX-inhibition may be effectively potentiated by COX-independent actions from Celecoxib and/or its (COX)-inactive metabolites, leading to relevant antitumor effects, on non-gastrointestinal tumors the action of Celecoxib is probably limited to COX-2 inhibition and, as a matter of fact, its efficacy is less pronounced and still controversial.

Overall, because of the misleading toxicity observed in vitro, the potential of Celecoxib as antitumor agent has been probably overestimated in comparison with other NSAIDs, while limited beneficial effects must be accurately weighted against unwanted risks, in particular cardiovascular toxicity associated with COX-2 inhibitors. For what concerns endocrine cancers, it is early to draw conclusions, considering the heterogeneity of these tumors and the limited literature on the subject. However, the available evidences do not support the idea of testing Celecoxib as a first choice in prevention or therapy, but suggest considering other NSAIDS as well, or combinations of NSAIDs, in pre-clinical models and clinical trials.