ABSTRACT
The metabolism of arachidonic acid through both cyclooxygenase (COX) and lipoxygenase (LOX) pathways leads to the generation of various biologically active eicosanoids. The expression of these enzymes varies across the progressive sequence from metaplasia-dysplasia to cancer, and thereby has been shown to regulate various aspects of tumor development. Pharmacologic and natural inhibitors of COX and LOXs have been shown to suppress carcinogenesis and tumor growth in a number of experimental models. Arachidonic acid metabolism potentially effect diverse biological phenomenon regulating processes such as cell growth, cell survival,
angiogenesis, cell invasion and metastatic potential. The influence of distinct COX and LOX isoforms, and their downstream metabolites, differ considerably with respect to their effect on both the individual mechanisms described and the tumor being examined. COX-2, 5-LOX and platelet type 12-LOX are generally considered proangiogenic, while 15-LOX-2 suppresses angiogenesis. In this chapter, we focus on the molecular mechanisms of angiogenesis and metastasis regulated by COX and LOX metabolism in some of the major cancers. We discuss the effects of downstream mediators of COX and LOX pathways on angiogenesis, focusing on the various steps regulating this process. Understanding the molecular mechanisms underlying the anti-angiogenic effect of specific or general COX and LOX inhibitors may lead to the design of biologically and pharmacologically targeted therapeutic strategies inhibiting these biologically active metabolites, which may ultimately prove useful in the treatment of cancer, either alone or in combination with conventional therapies.
