Abstract
Cyclooxygenase-2 (COX-2) is an important enzyme involved in prostaglandins biosynthesis from arachidonic acid. COX-2 is frequently overexpressed in human cancers and plays a major tumor promoting function. Accordingly, many efforts have been devoted to efficiently target the catalytic site of this enzyme in cancer cells, by using COX-2 specific inhibitors such as celecoxib. However, despite their potent anti-tumor properties, the myriad of detrimental effects associated to the chronic inhibition of COX-2 in healthy tissues, has considerably limited their use in clinic. In addition, increasing evidence indicate that these anti-cancerous properties are not strictly dependent on the inhibition of the catalytic site. These findings have led to the development of non-active COX-2 inhibitors analogues aiming at preserving the antitumor effects of COX-2 inhibitors without their side effects. Among them, two celecoxib derivatives, 2,5-Dimethyl-Celecoxib and OSU-03012, have been developed and suggested for the treatment of viral (e.g., recently SARS-CoV-2), inflammatory, metabolic diseases and cancers. These molecules display stronger anti-tumor properties than celecoxib and thus may represent promising anti-cancer molecules. In this review, we discuss the impact of these two analogues on cancerous processes but also their potential for cancer treatment alone or in combination with existing approaches.
Highlights
Chronic inflammation has been recognized as a critical tumor promoter [1]
Among the inflammatory mediators involved in carcinogenesis, arachidonic acid-derived lipid mediators such as prostaglandins contribute to tumor development by altering several cancerous hallmarks [2]
Other mechanisms associated to the chronic inhibition of COX-2 may contribute to this imbalance, including the increased LOX pathway, which promotes the synthesis of vasoconstrictive derivatives, such as leukotriene B4 (LTB4) by neutrophils [19,20]
Summary
Chronic inflammation has been recognized as a critical tumor promoter [1]. Among the inflammatory mediators involved in carcinogenesis, arachidonic acid-derived lipid mediators such as prostaglandins contribute to tumor development by altering several cancerous hallmarks [2]. In light of the dissociation between the antitumor properties of these molecules and the enzymatic activity of COX-2 [14], using non-active analogs may represent a wiser approach for cancer treatment Following this concept, several COX-2 specific inhibitors derivatives have been developed, such as celecoxib analogs, 2,5-dimethyl celecoxib and OSU-03012 (2-amino-N[4-[5-(2-phenanthrenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] phenyl]-acetamide). Other mechanisms associated to the chronic inhibition of COX-2 may contribute to this imbalance, including the increased LOX (lipoxygenase) pathway, which promotes the synthesis of vasoconstrictive derivatives, such as leukotriene B4 (LTB4) by neutrophils [19,20] Due to these deleterious effects, several COX-2 inhibitors have been retrieved from the market, such as rofecoxib in 1996 [21] (https://www.fda.gov/drugs/postmarket-drugsafety-information-patients-and-providers/vioxx-rofecoxib-questions-and-answers accessed on 29 April 2021) [22].
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