Pharmacological intervention of cyclooxygenase-2 and 5-lipoxygenase pathways. Impact on inflammation and cancer.
Eicosanoids are potent biologically active arachidonic acid-derived lipid mediators that are intimately involved in inflammation and cancer. Cyclooxygenase (COX), the key enzyme in prostaglandin (PG) biosynthesis, controls one of the major pathways of arachidonic acid metabolism and is the main target for non-steroidal anti-inflammatory drugs (NSAIDs). COX exists in two distinct isoforms, COX-1 and COX-2, the latter being primarily involved in inflammation and cell proliferation. For this reason, in recent years, selective COX-2 inhibitors, that achieve the same anti-inflammatory efficacy as traditional NSAIDs but minimize the risk of unwanted side-effects, have been developed. On the other hand, emerging information has appreciated the role of other arachidonic acid metabolic pathway (the 5-lipoxygenase (5-LO) pathway) in producing and maintaining inflammation. Moreover, it is now being perceived that COX-2 and 5-LO have converging functions not only in inflammation but also in cell proliferation and neo-angiogenesis. In this regard, there is evidence that COX-2 and 5-LO are co-expressed and up-regulated in a number of inflammatory and neoplastic disorders, and that COX-2 as well as 5-LO inhibitors have beneficial effects in inflammatory diseases and are being investigated as potential anticancer drugs. This review provides an overview and an update of the progress achieved in the knowledge of COX-2 and 5-LO pathways and their involvement in inflammation and cancer. It also proposes a model of integrated pharmacological intervention on these pathways and reviews the information available regarding the use of the novel dual COX-2/5-LO inhibitors that block both pathways equally well.
Clària
J
J
DNA Unit, Hospital Clínic, and Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Spain. jclaria@clinic.ub.es
Romano
M
M
D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism / Q000494:pharmacology*; D052246:Cyclooxygenase 2 Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D016859:Lipoxygenase Inhibitors; D009369:Neoplasms / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism
D052246:Cyclooxygenase 2 Inhibitors; D016859:Lipoxygenase Inhibitors; D001094:Arachidonate 5-Lipoxygenase