Inflammation, Cancer and Oxidative Lipoxygenase Activity are Intimately Linked

Abstract

Cancer and inflammation are intimately linked due to specific oxidative processes in the tumor microenvironment. Lipoxygenases are a versatile class of oxidative enzymes involved in arachidonic acid metabolism. An increasing number of arachidonic acid metabolites is being discovered and apart from their classically recognized pro-inflammatory effects, anti-inflammatory effects are also being described in recent years. Interestingly, these lipid mediators are involved in activation of pro-inflammatory signal transduction pathways such as the nuclear factor κB (NF-κB) pathway, which illustrates the intimate link between lipid signaling and transcription factor activation. The identification of the role of arachidonic acid metabolites in several inflammatory diseases led to a significant drug discovery effort around arachidonic acid metabolizing enzymes. However, to date success in this area has been limited. This might be attributed to the lack of selectivity of the developed inhibitors and to a lack of detailed understanding of the functional roles of arachidonic acid metabolites in inflammatory responses and cancer. This calls for a more detailed investigation of the activity of arachidonic acid metabolizing enzymes and development of more selective inhibitors.

Scheme 1

Oxidation reactions of lipoxygenases in the leukotriene (LT) biosynthesis pathways.

Figure 1

The roles of leukotrienes and acetylation in the expression of pro-inflammatory mediators through the NF-κB pathway. The activated cPLA2α produces arachidonic acid, which is further converted to LTA4 by the 5-LOX. LTA4 is then converted to LTB4 and cys-LTs and their binding to the leukotriene receptors activate the NF-κB pathway in leukocytes during inflammation. cPLA2α—cytosolic phospholipase A2-α; 5-LOX—5-lipoxygenase; LTA4—leukotriene A4; LTB4—leukotriene B4; Cys-LTs—cysteinyl leukotrienes; LTBR1/2—leukotriene B receptors 1 or 2; CysLTR1/2—cysteinyl leukotriene receptors 1 or 2; PI3K—phosphoinositide 3-kinase; PKC—protein kinase C; NEMO—NF-κB essential modulator; IκBα—inhibitor NF-κB; IKK—IκB kinase; NIK—NF-κB activation of inducing kinase; HAT—histone acetyltransferase. TNFα—tumor necrosis factor α; MIP—2-macrophage inflammatory protein-2; COX-2—cycloxygenas-2; iNOS—inducible nitric oxide synthase.

Scheme 2

Two lipoxygenase-based synthesis routes of lipoxins (LXs).

Figure 2

Lipoxygenase inhibitors.