Eicosanoids and cancer

Eicosanoids are 20-carbon bioactive lipids derived from the metabolism of polyunsaturated fatty acids, which can modulate various biological processes including cell proliferation, adhesion and migration, angiogenesis, vascular permeability and inflammatory responses. In recent years, studies have shown the importance of eicosanoids in the control of physiological and pathological processes associated with several diseases, including cancer. The polyunsaturated fatty acid predominantly metabolized to generate 2-series eicosanoids is arachidonic acid, which is the major n-6 polyunsaturated fatty acid found in animal fat and in the occidental diet. The three main pathways responsible for metabolizing arachidonic acid and other polyunsaturated fatty acids to generate eicosanoids are the cyclooxygenase, lipoxygenase and P450 epoxygenase pathways. Inflammation plays a decisive role in various stages of tumor development including initiation, promotion, invasion and metastasis. This review will focus on studies that have investigated the role of prostanoids and lipoxygenase-derived eicosanoids in the development and progression of different tumors, highlighting the findings that may provide insights into how these eicosanoids can influence cell proliferation, cell migration and the inflammatory process. A better understanding of the complex role played by eicosanoids in both tumor cells and the tumor microenvironment may provide new markers for diagnostic and prognostic purposes and identify new therapeutic strategies in cancer treatment.

Anopheles gambiae eicosanoids modulate Plasmodium berghei survival from oocyst to salivary gland invasion

Eicosanoids affect the immunity of several pathogen/insect models, but their role on the Anopheles gambiae response to Plasmodium is still unknown. Plasmodium berghei-infected mosquitoes were injected with an eicosanoid biosynthesis inhibitor, indomethacin (IN), or a substrate, arachidonic acid (AA), at day 7 or day 12 post-infection (p.i.). Salivary gland invasion was evaluated by sporozoite counts at day 21 p.i. IN promoted infection upon sporozoite release from oocysts, but inhibited infection when sporozoites were still maturing within the oocysts, as observed by a reduction in the number of sporozoites reaching the salivary glands. AA treatment had the opposite effect. We show for the first time that An. gambiae can modulate parasite survival through eicosanoids by exerting an antagonistic or agonistic effect on the parasite, depending on its stage of development.

An update on eicosanoids and inhibitors of cyclooxygenase enzyme systems.

There are 3 main enzymatic pathways for synthesis of eicosanoids from arachidonic acid, however, some compounds are also formed non-enzymatically. Among the enzymatic pathways, cyclooxygenase (COX) also known as prostaglandin synthase (PGHS), generates endoperoxides (PGG/H). These are converted into prostaglandins (PGs) and thromboxanes (TXs). The second pathway involves lipooxygenase (LOX) group of enzymes to provide hydroperoxyeicosatetraenoic acid (HpETEs) which in turn can be converted into leukotrienes (LTs), hepoxilins (HXs), trioxilins and lipoxins (LXs). The third pathway involves cytochrome P-450 which catalyses the formation of a number of monohydroxy fatty acids (hydroxyeicostetraenoic acids or HETEs) dihydroxy fatty acids (dihydroxyeicostetrienoic acids or DiHETrEs) and epoxyeicosatrienoic acids (EpETrEs: formerly called EETs). This system also provides leukotoxins. The non-enzymatic pathway leads to the formation of isoprostanes by free radical catalysed peroxidation of arachidonic acid. In addition, brain cells also convert arachidonic acid into arachidonylethanolamide (anandamide) which have the ability to bind to cannabinoid receptors. Most of these eicosanoids are either biologically active or are converted into metabolites which have biological activities. Cyclooxygenase is now known to exist in two separate isoforms which are called COX-1 and COX-2. While both isoforms catalyse the same reactions, the former is a constitutive enzyme and its activity is not markedly changed once the cell is fully grown. The later isoform is however inducible and its activity is several fold increased following the exposure of body cells to a number of stimuli and its contribution in the process of inflammation is now well documented. It is now believed that eicosanoids produced by COX-1 activity are essential for the physiological (house keeping) functions while those produced by COX-2 lead to various pathological changes in body tissues. Older nonsteroidal antiinflammatory drugs like aspirin and indomethacin are non selective inhibitors of COX activity and therefore, in addition to inhibiting COX-2 activity, inhibit the formation of eicosanoids by COX-1. The later are required for normal house keeping functions such as secretion of mucus for protection of gastrointestinal mucosa, maintenance of renal function and control of haemostasis. Use of older non-selective NSAIDs has been associated with a number of gastrointestinal, renal and other side effects. Recently drugs such as nimesulide and meloxicam with selective action on COX-2 have been discovered and introduced into medicine. Evidence available so far has indicated the low incidence of side effects with these drugs. While being useful for various arthritic and other conditions, it is unlikely that these drugs will replace aspirin for the cardiovascular disease.