Therapeutic implications of disorders of cell death signalling: membranes, micro‐environment, and eicosanoid and docosanoid metabolism

Abstract

Disruptions of cell death signalling occur in pathological processes, such as cancer and degenerative disease. Increased knowledge of cell death signalling has opened new areas of therapeutic research, and identifying key mediators of cell death has become increasingly important. Early triggering events in cell death may provide potential therapeutic targets, whereas agents affecting later signals may be more palliative in nature. A group of primary mediators are derivatives of the highly unsaturated fatty acids (HUFAs), particularly oxygenated metabolites such as prostaglandins. HUFAs, esterified in cell membranes, act as critical signalling molecules in many pathological processes. Currently, agents affecting HUFA metabolism are widely prescribed in diseases involving disordered cell death signalling. However, partly due to rapid metabolism, their role in cell death signalling pathways is poorly characterized. Recently, HUFA-derived mediators, the resolvins/protectins and endocannabinoids, have added opportunities to target selective signals and pathways. This review will focus on the control of cell death by HUFA, eicosanoid (C20 fatty acid metabolites) and docosanoid (C22 metabolites), HUFA-derived lipid mediators, signalling elements in the micro-environment and their potential therapeutic applications. Further therapeutic approaches will involve cell and molecular biology, the multiple hit theory of disease progression and analysis of system plasticity. Advances in the cell biology of eicosanoid and docosanoid metabolism, together with structure/function analysis of HUFA-derived mediators, will be useful in developing therapeutic agents in pathologies characterized by alterations in cell death signalling. AbbreviationsDHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; NSAID, nonsteroidal anti-inflammatory drug; PG, prostaglandin; AA, arachidonic acid; HUFA, highly unsaturated fatty acids with 4 or more bonds, for example, arachidonic, eicosapentaenoic and docosahexaenoic acids (4, 5 and 6 double bonds respectively); PUFA, polyunsaturated fatty acids, with 2 or more unsaturated C-C bonds; HUFA, highly unsaturated C20 fatty acid, with 3 or more unsaturated C-C bonds Many therapeutic agents influence cell death signalling and highly unsaturated fatty acid (HUFA) metabolism (Figure 1). These agents may act at the level of metabolic events affecting apoptosis, enzyme systems and cofactors, agents affecting cell cycle progression and DNA repair, and oncogene expression. Intracellularly, agents affecting organelles and the mitochondrial intrinsic pathway, endoplasmic reticulumassociated stress pathways and lysosomal autophagy can have profound effects on cell death. There has also been development of agents affecting transcellular signalling via the extrinsic pathway, oxidative stress, growth factors and lipid mediators, ion and metabolite flux, adhesion and migration.

Docosahexaenoic acid regulates gene expression in HUVEC cells treated with polycyclic aromatic hydrocarbons

“…The n-3/n-6 PUFA content of cell and organelle membranes, as well as membrane micro-domains strongly influence membrane function and numerous cellular processes such as cell death and survival (Davidson et al, 2012;Dendelé et al, 2014). In the presented study there were significant changes in the FAs profile in all groups of cells, those PAHs-activated and those supplemented with DHA in relation to the control group.…”

“…An important mechanism for the healthpromoting effects of n-3 PUFAs is that they suppress the proinflammatory metabolism of arachidonic acid (AA). Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) inhibit the formation of AA derivatives via multiple mechanisms (Davidson et al, 2012;Colas et al, 2014;Spite et al, 2014).…”

Docosahexaenoic acid attenuates in endocannabinoid synthesis in RAW 264.7 macrophages activated with benzo(a)pyrene and lipopolysaccharide

“…Inflammation is associated with many disorders such as inflammatory diseases, metabolic syndrome, atherosclerosis and cancer (Clària et al, 2011;Davidson et al, 2012;Calder, 2015;Gdula-Argasi nska et al, 2013, 2015a,b, 2016. Mechanisms to curtail the inflammatory response and promote its resolution are of immense interest (Clària et al, 2011;Meijerink et al, 2011;Serhan and Petasis, 2011;Davidson et al, 2012;Wahli and Michalik, 2012;Fritsche, 2015).…”

“…Many of the downstream products of UNSFA are bioactive compounds controlling physiological functions, metabolism, homeostasis, and are also involved in the inflammation and immunity that relates to the pathology of various diseases. Lipid mediators also play a fundamental role as signaling molecules of a variety of cellular biochemical cascades including free radicals (Serhan and Petasis, 2011;Davidson et al, 2012;Spite et al, 2014).…”

Effect of ω-3 polyunsaturated fatty acids on the functional activity of monooxygenase system in the liver microsomal fraction of tumor-bearing rats

“…Один з можливих механізмів ан-тиканцерогенної дії ω-3 ПНЖК -їх конверсія в оксигеновані похідні цитохром Р450-залежним метаболічним шляхом. Утворені метаболіти прямо або опосередковано впливають на пролі-ферацію і ріст пухлинних клітин [16], водно-…”