8-11-14-eicosatrienoic-acid and Cell-Transformation--Neoplastic

Inflammation and angiogenesis in the tumor microenvironment are increasingly implicated in tumorigenesis. Endogenously produced lipid autacoids, locally acting small-molecule mediators, play a central role in inflammation and tissue homeostasis. These lipid mediators, collectively referred to as eicosanoids, have recently been implicated in cancer. Although eicosanoids, including prostaglandins and leukotrienes, are best known as products of arachidonic acid metabolism by cyclooxygenases and lipoxygenases, arachidonic acid is also a substrate for another enzymatic pathway, the cytochrome P450 (CYP) system. This eicosanoid pathway consists of two main branches: ω-hydroxylases which converts arachidonic acid to hydroxyeicosatetraenoic acids (HETEs) and epoxygenases which converts it to four regioisomeric epoxyeicosatrienoic acids (EETs; 5,6-EET, 8,9-EET, 11,12-EET, and 14,15-EET). EETs regulate inflammation and vascular tone. The bioactive EETs are produced predominantly in the endothelium and are mainly metabolized by soluble epoxide hydrolase to less active dihydroxyeicosatrienoic acids. EET signaling was originally studied in conjunction with inflammatory and cardiovascular disease. Arachidonic acid and its metabolites have recently stimulated great interest in cancer biology. To date, most research on eicosanoids in cancer has focused on the COX and LOX pathways. In contrast, the role of cytochrome P450-derived eicosanoids, such as EETs and HETEs, in cancer has received little attention. While CYP epoxygenases are expressed in human cancers and promote human cancer metastasis, the role of EETs (the direct products of CYP epoxygenases) in cancer remains poorly characterized. In this review, the emerging role of EET signaling in angiogenesis, inflammation, and cancer is discussed.

Topics: 8,11,14-Eicosatrienoic Acid; Animals; Cell Transformation, Neoplastic; Cytochrome P-450 Enzyme System; Humans; Inflammation; Neoplasms; Neovascularization, Pathologic; Signal Transduction; Tumor Microenvironment

Epoxyeicosatrienoic acids (EETs) and the cytochrome P450 epoxygenase CYP2J2 promote tumorogenesis in vivo and in vitro via direct stimulation of tumor cell growth and inhibition of tumor cell apoptosis. Herein, we describe a novel mechanism of inhibition of tumor cell apoptosis by EETs. In Tca-8113 cancer cells, the antileukemia drug arsenic trioxide (ATO) led to the generation of reactive oxygen species (ROS), impaired mitochondrial function, and induced apoptosis. 11,12-EET pretreatment increased expression of the antioxidant enzymes superoxide dismutase and catalase and inhibited ATO-induced apoptosis. 11,12-EET also prevented the ATO-induced activation of p38 mitogen-activated protein kinase, c-Jun NH(2)-terminal kinase, caspase-3, and caspase-9. Therefore, 11,12-EET-pretreatment attenuated the ROS generation, loss of mitochondrial function, and caspase activation observed after ATO treatment. Moreover, the CYP2J2-specific inhibitor compound 26 enhanced arsenic cytotoxicity to a clinically relevant concentration of ATO (1-2 μM). Both the thiol-containing antioxidant, N-acetyl-cysteine, and 11,12-EET reversed the synergistic effect of the two agents. Taken together, these data indicate that 11,12-EET inhibits apoptosis induced by ATO through a mechanism that involves induction of antioxidant proteins and attenuation of ROS-mediated mitochondrial dysfunction.

Topics: 8,11,14-Eicosatrienoic Acid; Antineoplastic Agents; Antioxidants; Apoptosis; Arsenic Trioxide; Arsenicals; Caspase Inhibitors; Caspases; Cell Line, Tumor; Cell Transformation, Neoplastic; Cytochrome P-450 CYP2J2; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Drug Screening Assays, Antitumor; Drug Synergism; Enzyme Activation; HEK293 Cells; Humans; Indazoles; Membrane Potential, Mitochondrial; Mitochondria; Nitrofurans; Oxides; Reactive Oxygen Species

A number of fatty acids have been shown to inhibit the growth of malignant cells in vitro. In particular, gamma-linolenic acid (GLA) has been proposed to act as a precursor for the production of prostanoids especially prostaglandin E1 (PGE1). To test this hypothesis, the effects of GLA on cultured human breast carcinoma cells were compared with those of dihomo-gamma-linolenic acid (DGLA) the metabolite of GLA and the immediate precursor of PGE1. The influence of ethanol (which has been shown to enhance conversion of DGLA to PGE1) on the actions of each of the fatty acids was also investigated. In contrast to the inhibitory effects observed with all concentrations of GLA cell growth was promoted by the presence of 50 micrograms DGLA. Ethanol reduced the action of both GLA and DGLA possibly due to some physicochemical reaction between the alcohol and the fatty acids. The fact that the actions of GLA were not mimicked by DGLA which is the next step towards PG production casts doubt upon the role of PGE1 as mediator of the effects which have been observed with GLA in malignant cells.

Topics: 8,11,14-Eicosatrienoic Acid; Adult; Animals; Breast Neoplasms; Cell Transformation, Neoplastic; Cells, Cultured; Cytoplasmic Granules; Drug Combinations; Ethanol; Fatty Acids, Unsaturated; Female; gamma-Linolenic Acid; Growth Inhibitors; Growth Substances; Humans; Linolenic Acids; Male; Mice