New Approaches to the Modulation of the Cyclooxygenase-2 and 5-Lipoxygenase Pathways

Abstract

The eicosanoid family comprises a number of biologically active lipid mediators involved in the regulation of inflammation and cancer cell growth. Eicosanoid biosynthesis is usually initiated by the release of arachidonic acid (AA) from membrane phospholipids in response to the interaction of a phospholipase-A(2) (PLA(2)) stimulus with a receptor on the cell membrane. The free released AA is subsequently metabolized by three major enzymatic pathways: the cyclooxygenase (COX), lipoxygenase (LO) and cytochrome P450-dependent pathways. The COX pathway transforms AA into prostaglandins (PGs) and is of particular clinical relevance because it is the main target for non-steroidal anti-inflammatory drugs (NSAIDs). Of interest, COX-2, one of the two COX isoforms, is primarily involved in inflammation and cancer and for this reason selective COX-2 inhibitors have been developed. The efficacy of these compounds is similar to that of traditional NSAIDs but with a lower risk of gastrointestinal toxicity and bleeding. On the other hand, emerging information has recognized the role of other AA metabolites derived from the 5-LO pathway, the leukotrienes (LTs), in mediating and maintaining inflammation. Consequently, drugs able to inhibit 5-LO are now included among the effective pharmacological therapies, especially in asthma and allergic inflammation. Moreover, COX-2 and 5-LO pathways appear to act in parallel in the regulation of cell proliferation and neo-angiogenesis and both COX-2 and 5-LO inhibitors are being investigated as potential anticancer drugs. This review article will update the progress achieved in the knowledge of COX-2 and 5-LO and discuss the emerging approaches for the pharmacological modulation of these pathways.

Melatonin: A pleiotropic molecule regulating inflammation

“…The inflammatory response starts with an insult that activates and recruits leukocytes to the inflamed tissue through recruitment of different molecular mediators; an important role in the early phase is played by phospholipase A2 (PLA2), which cleaves membrane phospholipids liberating membrane bound arachidonic acid (AA); arachidonic acid is then processed by cyclooxygenases 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 -8 -(COX) and LOX to produce key inflammatory mediators such as prostaglandins and leukotrienes [87], respectively. After experimental inflammation induction in vivo and ex vivo, melatonin was shown to prevent or reduce the inflammatory-derived activation of PLA2 [88] , LOX [89] and COX [90].…”

Dietary polyunsaturated fatty acids as inducers of apoptosis: implications for cancer

“…Most of these metabolites are biologically active lipids exerting potent pro-inflammatory actions [97] and are recognized as positive key regulators of cell survival, neoangiogenesis and metastasis [98,99]. For this reason, agents that specifically target these lipid mediators or the enzymes that catalyze their formation starting from AA (COX and LOX) have been investigated as potential anticancer drugs [100]. On the other hand, it has been observed that the addition of exogenous unesterified AA to different cancer cell lines inhibits cell growth and induces apoptosis [101].…”

15-oxo-Eicosatetraenoic Acid, a Metabolite of Macrophage 15-Hydroxyprostaglandin Dehydrogenase That Inhibits Endothelial Cell Proliferation

“…Bioactive lipid mediators are increasingly being recognized as important endogenous regulators of angiogenesis (Gonzá-lez-Périz and Clà ria, 2007). One of the major cascades of bioactive lipid mediator production involves the release of AA from membrane phospholipids followed by COX-2-mediated formation of eicosanoids .…”