Effect of ω-3 and ω-9 fatty acid rich oils on lipoxygenases and cyclooxygenases enzymes and on the growth of a mammary adenocarcinoma model.

BACKGROUND: Nutritional factors play a major role in cancer initiation and development. Dietary polyunsaturated fatty acids (PUFAs) have the ability to induce modifications in the activity of lipoxygenase (LOX) and cyclooxygenase (COX) enzymes that affect tumour growth. We studied the effect of two diets enriched in 6% Walnut and Peanut oils that are rich in ω-3 and ω9 PUFAs respectively on a murine mammary gland adenocarcinoma as compared with the control (C) that received commercial diet. RESULTS: Peanut oil enriched diet induced an increase in membrane arachidonic acid (AA) content and the cyclooxygenase enzyme derived 12-HHT (p < 0.05) and simultaneously showed decrease in 12-LOX, 15-LOX-2, 15-LOX-1 and PGE activities (p < 0.05) that corresponded to higher apoptosis and lower mitosis seen in this group (p < 0.05). Furthermore, Peanut oil group showed lower T-cell infiltration (p < 0.05), number of metastasis (p < 0.05) and tumour volume (p < 0.05) and longer survival rate compared to other groups. CONCLUSIONS: The results of the present study showed that Peanut oil-enriched diet protects against mammary cancer development by modulating tumour membrane fatty acids composition and LOX and COX enzyme activities.

Primers on molecular pathways - lipoxygenases: their role as an oncogenic pathway in pancreatic cancer.

Different evidence supports a functional role of enzymes involved in lipid metabolic pathways, such as lipoxygenases (LOXs) and their metabolite derivatives, in carcinogenesis. LOX enzymes catalyze the dioxygenation of arachidonic acid into hydroxyperoxyeicosatetraenoic acids, which is followed by their conversion to their corresponding eicosanoids as hydroxyeicosatetraenoic acids, leukotrienes, lipoxins and hepoxilins, which in turn act as cellular messengers. Subcellular LOX enzyme localization varies according to the LOX and cellular type regulating different cell functions. LOX enzymes or their products may exert their biological effects in different modes, either intracellular or in other cells. Numerous clinical studies on expression of LOXs in human tumors as well as in animal models indicate different roles of distinct LOX isoforms in carcinogenesis. In fact, different LOXs exhibit either protumorigenic or antitumorigenic activities and modulate the tumor response in a tissue-specific manner. Moreover, the LOX pathways are involved in the spread and metastasis of several cancers, including pancreas, through the activation of several cellular signaling pathways which modify gene expression affecting cellular proliferation, survival, migration and extracellular matrix production. In this review we focus on the important role and different mechanisms of action of LOX pathways in the regulation of pancreatic cancer initiation and progression. A novel approach for pancreatic cancer chemoprevention would involve targeting LOX activities, alone or in combination with other pathways as a major anticancer strategy.

Experimental uterine eosinophilia in the rat. The role of some inhibitors of arachidonic acid metabolism.

The mechanism of estrogen induced eosinophilia is not well understood. It has been proposed that type II estrogen receptors, present both in eosinophils and uterine tissues, can act as anchorage mechanism for the attachment of eosinophils within the uterus. However an explanation based on the existence of chemotactic mediators is more likely. We studied the effects of the lipoxygenase inhibitor BW755 and two different doses of indomethacin in a model of acute uterine eosinophilia promoted by 17-beta-estradiol in young rats; simultaneously estrogen receptors were studied with immunocytochemical methods using monoclonal antibodies. BW755 and a high dose of indomethacin sharply reduced the estrogen induced eosinophilia, whereas a low dose of indomethacin enhanced the steroid effect. No estrogen receptors were found with immunohistochemical methods neither in eosinophils nor in endothelial cells in any of the groups. A role for the lipoxygenase products of arachidonic acid, mainly leukotrine B4 as the chemical mediators responsible of eosinophil chemotaxis in be estrogen primed uterus is suggested.

The involvement of oxytocin in ovulation and in the outputs of cyclo-oxygenase and 5-lipoxygenase products from isolated rat ovaries.

The effects on ovulation of a specific anti-oxytocin rabbit serum (anti-OT) (50.0 microliters) given by intrabursal injection into the right ovaries of etherized adult female rats at proestrus, were explored by counting the number of ovulated ova present within the right oviducts. Left ovaries were not treated and served as control ovaries. Control rats were treated with male normal rabbit serum (NRS) (50.0 microliters) given by intrabursal injections into the right ovaries of animals at proestrus. Ovulation was induced by injection of human chorionic gonadotrophin (hCG). Anti-OT administered into the right ovarian bursae of proestrous rat ovaries evoked a significant 51% inhibition of ovulation in comparison with that observed in control non-injected left ovaries (p less than 0.01). Also, when the ovulation of right ovaries injected with anti-OT was compared with that of left ovaries injected with NRS, the number of ovulated ova in the right side was significantly smaller (30%) than on the contralateral side (p less than 0.02). However, in rats pre-treated with hCG the intrabursal injection of oxytocin (OT) (50.0 mU/ml) into right and left ovaries failed to alter the number of ovulated ova compared with that of rats receiving intrabursal injections of saline. The basal control and the OT-evoked synthesis and release of endogenous prostaglandin E2 (PGE2) and PGF2 alpha were explored in ovaries isolated from prepuberal rats injected with pregnant mare's serum gonadotrophin (PMSG), two days prior to sacrifice. OT augmented the basal release of PGF2 alpha but did not influence that of PGE2. Moreover, the conversion of exogenous 14C-arachidonic acid (14C-AA) into different prostanoids and into 5-HETE, in the presence and in the absence of added OT (50.0 mU/ml), was studied in rat ovaries isolated in proestrus. The challenge with OT augmented the basal synthesis and release of PGF2 alpha and of 5-HETE from 14C-AA, but failed to influence the formation of products generated via the cyclo-oxygenase pathway, namely 6-keto-PGF1 alpha, PGE2 and thromboxane B2 (TXB2). Therefore, the present results suggest that ovarian OT may play a role in the ovulatory process, via generation of PGF2 alpha to enhance contractions of ovarian smooth muscle and of 5-HETE to promote follicular collagenolysis.

Involvement of 5-lipoxygenase pathway in norepinephrine stimulation of rat pineal melatonin synthesis.

The effect of lipoxygenase inhibition, leukotriene agonists and antagonists, and 5-hydroxy-6,8,11,14-eicosatetraenoic acid (5-HETE) was examined in the rat pineal gland in organ culture. To study melatonin secretion pineal explants were incubated for 6 h in tissue culture medium 199 with the different drugs. Melatonin concentration in the pineal gland and the medium was measured by RIA. Exposure of explants to norepinephrine (NE) brought about a 2- to 5-fold increase in both parameters, an effect that was reduced but not abolished, by the lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA; 10(-5) M). Lilly 171883 (10(-5) M) or FPL 55712 (10(-5) M; both antagonists of leukotrienes) reduced NE-induced melatonin production. Neither NDGA nor Lilly 171883 affected melatonin production in the absence of NE. Leukotrienes C4 and D4 increased melatonin release to the media at all concentrations tested (1-1,000 nM) with a maximum effect at 1 nM (leukotriene C4) and 10 nM (leukotriene D4). Significantly higher tissue melatonin concentrations as compared to controls were observed after exposure of pineal explants to 1 and 100 nM of leukotriene C4, or 100 nM of leukotriene D4. Another 5-lipoxygenase metabolite, 5-HETE, increased pineal melatonin content at concentrations of 1, 10 and 100 nM whereas only 1,000 nM stimulated melatonin release. These results suggest that the 5-lipoxygenase pathway plays a significant role in NE-stimulated melatonin production by the rat pineal gland.