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At least 19 recordsLinked to original sources
PubMed1982

Inhibition of 12-O-tetradecanoylphorbol-13-acetate-induced epidermal ornithine decarboxylase activity by phospholipase A2 inhibitors and lipoxygenase inhibitor.

Application of 12-O-tetradecanoylphorbol-13-acetate (TPA; 20 nmol/mouse), a tumor-promoting agent, to mouse skin results in an induction of epidermal ornithine decarboxylase (ODC; EC 4.1.1.17). Induction of ODC by TPA was inhibited by treatment of skin with indomethacin (1.12 mumol/mouse), a cyclooxygenase inhibitor, and the ODC activity suppressed by indomethacin was completely restored by concurrent application of prostaglandin E2 (PGE2) (140 nmol/mouse) as described first by Verma et al. (Cancer Res., 40: 308-315, 1980). Treatment of mice with tetracaine (20 and 100 mumol/mouse), a nonspecific phospholipase A2 inhibitor, inhibited the induction of ODC by TPA. More specific phospholipase A2 inhibitors, mepacrine (20 mumol/mouse) and p-bromophenacyl bromide (10 mumol/mouse), also inhibited the ODC induction. The TPA-induced ODC inhibited by mepacrine was not restored by the treatment of mice with PGE2. TPA-induced ODC inhibited by either mepacrine or p-bromophenacyl bromide was partially but significantly restored by treatment with arachidonic acid (1 to 40 mumol/mouse). Neither PGE2 nor arachidonic acid alone could induce the epidermal ODC. Treatment of mice with nordihydroguaiaretic acid (10 to 90 mumol/mouse), a lipoxygenase inhibitor, also inhibited the induction of ODC by TPA. These results strongly indicate that the stimulation of phospholipase A2 activity is a crucial process in inducing mouse epidermal ODC by TPA and not only cyclooxygenase product (i.e., PGE2) but also lipoxygenase product(s) are involved in the mechanism of ODC induction. Our present data also suggest that the above arachidonate metabolites are essential but not sufficient factors for the TPA-stimulated induction of ODC.

Animals↗
PubMed2006

Antioxidant and anti-inflammatory activity of aryl-acetic and hydroxamic acids as novel lipoxygenase inhibitors.

Lipoxygenase plays an essential role in the biosynthesis of the leukotrienes. Leukotrienes, as LO metabolites of arachidonic acid (AA), have been implicated as mediators in the pathophysiology of inflammatory diseases, host defense reactions and to play important role in the propagation of the diseases states, exacerbating the local events and ultimately leading to tissue damage. Simple stable molecules containing the hydroxamic acid functionality have been shown to inhibit 5-lipoxygenase. In fact, several hydroxamates are orally active inhibitors of the enzyme as determined by their ability to block the biosynthesis of leukotriene in vivo. In order to establish the inhibitory utility of simple hydroxamates several omega-phenylalkyl and omega-naphthylalkyl hydroxamic acids were synthesized. In an attempt to expand and delineate these results we tried to synthesize some more for a further pharmacochemical study. Since lipophilicity is a significant physicochemical property determining distribution, bioavailability, metabolic activity and elimination, we tried to determine experimentally their lipophilicity from RPTLC method. The compounds are tested in vitro on: a) soybean lipoxygenase inhibition, b) interaction with 1,1-diphenyl-2-picryl-hydrazyl (DPPH) stable free radical, c) the HO* radical mediated oxidation of DMSO, d) inhibition of lipid peroxidation, e) scavenging of superoxide anion radicals f) interaction with glutathione and g) in vivo for the inhibition of carrageenin induced rat paw edema. The compounds have shown important antioxidant activity, medium anti-inflammatory activity and potent inhibition of soybean lipoxygenase as a result of their physichochemical features.

Acetates↗
PubMed2002

Inhibition of peroxisome proliferator-activated receptor (PPAR)-mediated keratinocyte differentiation by lipoxygenase inhibitors.

Lipoxygenase (LOX) metabolites from arachidonic acid and linoleic acid have been implicated in atherosclerosis, inflammation, keratinocyte differentiation and tumour progression. We previously showed that peroxisome proliferator-activated receptors (PPARs) play a role in keratinocyte differentiation and that the PPARalpha ligand 8S-hydroxyeicosatetraenoic acid is important in this process. We hypothesized that blocking LOX activity would block PPAR-mediated keratinocyte differentiation. Three LOX inhibitors, nordihydroguaiaretic acid, quercetin and morin, were studied for their effects on primary keratinocyte differentiation and PPAR activity. All three LOX inhibitors blocked calcium-induced expression of the differentiation marker keratin 1. In addition, activity of a PPAR-responsive element was inhibited in the presence of all three inhibitors, and this effect was mediated primarily through PPARalpha and PPARgamma. LOX inhibitors decreased the activity of a chimaeric PPAR-Gal4-ligand-binding domain reporter system and this effect was reversed by addition of PPAR ligands. Ligand-binding studies revealed that the LOX inhibitors bind directly to PPARs and demonstrate a novel mechanism for these inhibitors in altering PPAR-mediated gene expression.

Animals↗
PubMed1986

Studies on lipoxygenase inhibitors. II. KF8940 (2-n-heptyl-4-hydroxyquinoline-N-oxide), a potent and selective inhibitor of 5-lipoxygenase, produced by Pseudomonas methanica.

Pseudomonas methanica KY4634 was found to produce 5-lipoxygenase inhibitor designated KF8940, MY12-62a and MY12-62c. The inhibitors were purified by solvent extraction, silica gel column chromatography, reversed-phase low pressure liquid chromatography and crystallization. The chemical structures of KF8940, MY12-62a and MY12-62c were determined to be 2-n-heptyl-4-hydroxyquinoline-N-oxide, 2-n-heptyl-4-hydroxyquinoline and 3-n-heptyl-3-hydroxy-1,2,3,4-tetrahydroquinoline-2,4-dione, respectively, on the basis of their physico-chemical properties. Among them, KF8940 was the most potent inhibitor. The compound inhibited 5-lipoxygenase of rat basophilic leukemia cells in a dose-dependent manner and the half maximal inhibitory concentration (IC50) was 1.5 X 10(-7) M. At this concentration, KF8940 did not inhibit bovine platelet 12-lipoxygenase and cyclooxygenase, and the IC50 values for these enzyme were 3.5 X 10(-5) M and 1.7 X 10(-4) M, respectively. The results indicated that KF8940 is a potent and selective inhibitor of 5-lipoxygenase. The IC50 value of MY12-62c for 5-lipoxygenase was 1.9 X 10(-5) M and that of MY12-62a was 1.9 X 10(-5) M.

Arachidonate Lipoxygenases↗
PubMed1986

Studies on lipoxygenase inhibitors. I. MY3-469 (3-methoxytropolone), a potent and selective inhibitor of 12-lipoxygenase, produced by Streptoverticillium hadanonense KY11449.

Streptoverticillium hadanonense KY11449 was found to produce a 12-lipoxygenase inhibitor MY3-469. The compound was purified by chromatography on Diaion HP-10, charcoal, Sephadex LH-20 and crystallization. The chemical structure of MY3-469 was determined to be 3-methoxytropolone on the basis of its physico-chemical properties. The half maximal inhibitory concentration (IC50) of MY3-469 against bovine platelet 12-lipoxygenase was 1.8 X 10(-6)M. The compound did not inhibit bovine platelet cyclooxygenase at 10(-3)M and showed weak inhibition (IC50 2.8 X 10(-4)) against 5-lipoxygenase of rat basophilic leukemia cells. The results indicate that MY3-469 is a potent and selective inhibitor of 12-lipoxygenase.

Actinomycetales↗
PubMed1992

Effects of a 5-lipoxygenase inhibitor, AA861, on lipoxygenase metabolism and superoxide anion generation by human polymorphonuclear leukocytes--potentiation of superoxide anion generation by LTB4.

We studied the influence of a selective 5-lipoxygenase inhibitor, AA861, on the generation of the superoxide anion (O2-) and the lipoxygenase metabolites by human polymorphonuclear leukocytes (PMN). PMN produce O2- in a dose-dependent manner following stimulation with arachidonic acid (AA), leukotriene B4 (LTB4), or C5a. When PMN were stimulated with one of those three agents in the presence of high doses of AA861 (1-10 micrograms/ml), a significant reduction of O2- release was observed. In contrast, the generation of O2- by PMN stimulated by LTB4 was potentiated at lower concentrations of AA861 (0.025-0.25 micrograms/ml). However, stimulation with AA or C5a did not influence O2- generation in the presence of AA861 at the same concentration range. Furthermore, treating the PMN with the cyclooxygenase inhibitor, acetylsalicylic acid, did not potentiate the generation of O2- by stimulation with LTB4 over a wide range of concentrations. Quantification of lipoxygenase metabolites by reverse-phase high-performance liquid chromatography revealed that a high concentration of AA861 (0.5-5 micrograms/ml) completely inhibited the production of LTB4 and its omega-oxidative metabolites by PMN following stimulation with 100 microM AA, but only partially inhibited that of 5-hydroxyeicosatetraenoic acid (5-HETE). AA861 at a concentration of 5 micrograms/ml significantly increased the production of 15-HETE by PMN following the same stimulation. AA861 did not influence catabolism of LTB4 added to the reaction mixture to its omega-oxidative products by PMN over a wide range of concentrations. These findings suggest that the inhibition of 5-lipoxygenase metabolism may stimulate 15-lipoxygenase in human PMN.(ABSTRACT TRUNCATED AT 250 WORDS)

Anions↗
PubMed1998

Inhibitory effects of nabumetone, a cyclooxygenase-2 inhibitor, and esculetin, a lipoxygenase inhibitor, on N-methyl-N-nitrosourea-induced mammary carcinogenesis in rats.

We investigated the modifying effects of nabumetone, a relatively selective cyclooxygenase-2 inhibitor, and esculetin, a lipoxygenase inhibitor, on N-methyl-N-nitrosourea(MNU)-induced mammary carcinogenesis in female Sprague-Dawley rats. A total of 124 rats, 6 weeks old, were divided into 6 groups. At 50 days of age, groups 1, 2, and 3 were treated with MNU (50 mg/kg body weight) by subcutaneous injection. From the age of 8 weeks, groups 2 and 4 were given 0.03% nabumetone in the diet and groups 3 and 5 were given 0.03% esculetin in the diet. All rats were necropsied at the termination (25 weeks after the start of experiment). The incidence and multiplicity of neoplasms in group 2 were significantly smaller than those in group 1 (P < 0.005 and P < 0.001, respectively). The incidence of neoplasms in group 3 was also significantly smaller than that in group 1 (P < 0.05). These results indicate that the intake of nabumetone or esculetin during the time corresponding to the post initiation phase has a chemopreventive effect on MNU-induced mammary carcinogenesis in rats.

Animals↗
PubMed1989

Protective effects of a thromboxane synthetase inhibitor, a thromboxane antagonist, a lipoxygenase inhibitor and a leukotriene C4, D4 antagonist on myocardial injury caused by acute myocardial infarction in the canine heart.

We studied the effects of a thromboxane A2 synthetase inhibitor (RS-5186), a thromboxane A2 antagonist (ONO-3708), a 5-lipoxygenase inhibitor (AA-861) and a peptidoleukotriene antagonist (ONO-1078) on infarct size, polymorphonuclear leukocyte infiltration, gross myocardial hemorrhage and arrhythmias in the canine coronary occlusion (2 hour)-reperfusion model (5 hour). The infarct size and risk area were determined by a double staining technique. Thirty minutes prior to occluding the coronary arteries, dogs were randomly assigned to one of the following five groups: the thromboxane A2 synthetase inhibitor group (n = 11) receiving RS-5186 10 mg/kg i.v., the thromboxane A2 antagonist group (n = 12) receiving continuous intravenous infusion of ONO-3708 1 microgram/kg/min, the lipoxygenase inhibitor group (n = 11) receiving AA-861 3 mg/kg i.v., the peptidoleukotriene antagonist group (n = 11) receiving continuous intravenous infusion of ONO-1078 1 microgram/kg/min and the vehicle control group (n = 15). Except for ONO-3708, all the other drugs reduced the infarct size (RS-5186: 26.3 +/- 2.4% of risk area (mean +/- SEM), AA-861: 21.8 +/- 1.3%, ONO-1078: 22.5 +/- 4.4% vs control: 54.0 +/- 6.4%, p less than 0.01 respectively) as well as reducing the area of gross myocardial hemorrhage (RS-5186: 3.9 +/- 2.6% of infarct size, AA-861: 5.1 +/- 2.4%, ONO-1078: 5.2 +/- 2.5% vs control: 22.3 +/- 3.9%, p less than 0.01 respectively). RS-5186 and AA-861 reduced the intensity of polymorphonuclear leukocyte infiltration into the infarcted area, however, neither ONO-3708 nor ONO-1078 had any significant influence.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1996

Suppression of human cancer cell proliferation by lipoxygenase inhibitors and gamma-radiation in vitro.

The effects of inhibitors of arachidonic acid oxidative metabolism, gamma-radiation and/or their combinations on proliferation and cell cycle were studied in human breast carcinoma HS578T and monoblastoid U937 cell lines. While piroxicam an inhibitor of cyclooxygenase pathway, had no significant effects on cell proliferation, inhibitors of lipoxygenase pathway, nordihydroguaiaretic acid and esculetin, suppressed [3H]-thymidine incorporation and cell growth. The latter agents also differed in their modulation of cell cycle parameters depending on the cell line and the time of treatment. When the cells were preirradiated with gamma radiation (5 Gy) and treated with the drugs (at concentrations 50 mumol/l and higher) the effects on cell proliferation were mostly additive. On the other hand, the results suggest that antiproliferative effects could be significantly strengthened when lower doses (25 mumol/l) of lipoxygenase inhibitors were combined with a low dose (1 Gy) of gamma-radiation. Experiments monitoring the reversibility of the effects after single or combined treatment with the agents showed that irradiation suppressed the ability of U937 cells to restore cell proliferation, and that these effects may be strenghtened by esculetin. In conclusion, our results (1) suggest that the lipoxygenase pathway plays a significant role in proliferation of cancer HS578T and U937 cells in vitro, and (2) implicate the possibility of more effective antiproliferative effects after combined treatment of cells with gamma-radiation and lipoxygenase inhibitors.

Breast Neoplasms↗
PubMed1992

Lipoxygenase inhibitors but not site specific 5-lipoxygenase blockers protect against endotoxic shock and inhibit production of tumor necrosis factor.

In the present study it was found that lipoxygenase inhibitors prevent LPS-, but not tumor necrosis factor alpha (TNF alpha)-evoked lethality. The specific 5-lipoxygenase inhibitors (MK-886, CGS-8515) were uneffective in endotoxin-induced shock. The 5-lipoxygenase inhibitors interfered with LTC4 formation in macrophages while they did not affect endotoxin induced TNF alpha-formation, neither in cell cultures nor in mice. The potency of other, less specific lipoxygenase blockers to suppress TNF alpha formation correlated quantitatively with their ability to interfere with 13-HODD synthesis. Based on the fact that a tight correlation exists between inhibition of TNF alpha synthesis and 13-HODD formation, this product might be important for TNF alpha formation.

Animals↗
PubMed1998

Studies on 5-lipoxygenase inhibitors. II. Discovery, optical resolution and enantioselective synthesis of FR110302, a highly potent non-redox type 5-lipoxygenase inhibitor.

A novel series of 2,2-dialkyl-5-(2-quinolylmethoxy)-1,2,3, 4-tetrahydro-1-naphthols was synthesized and evaluated as 5-lipoxygenase (5-LO) inhibitors. Systematic optimization led to identification of several highly potent non-redox type 5-LO inhibitors with nanomolar IC50s as racemic mixtures. Optical resolution of racemate 50 indicated that its 5-LO inhibitory activity was enantiospecific and due to the (+)-enantiomer. An efficient synthetic route to the (+)-enantiomers via asymmetric reduction of tetralone intermediates was established. The best compound, (+)-2,2-dibutyl-5-(2-quinolylmethoxy)-1,2,3,4-tetrahydro-1-naphtho l (FR110302, (+)-50), showed potent inhibitory activity against leukotriene (LT) biosynthesis by intact neutrophiles in rats (IC50 4.9 nM) and in humans (IC50 40 nM). Furthermore oral administration of FR110302 significantly inhibited neutrophil migration in the rat air pouch model at 1 mg/kg.

Anaphylaxis↗
PubMed1989

Lipoxygenase inhibitors suppress formation of tumor necrosis factor in vitro and in vivo.

The LPS induced synthesis of tumor necrosis factor in macrophage cultures, as determined in a fibroblast cytolysis assay was found to be effectively blocked by inhibitors of lipoxygenases. Likewise, the presence of tumor necrosis factor in serum of D-galactosamine sensitized mice after challenge with endotoxin was suppressed by the lipoxygenase inhibitors. Indomethacin, a blocker of cycclooxygenase was neither in vivo nor in vitro effective in the prevention of the endotoxin-induced synthesis of TNF. From LPS-treated macrophages we were able to isolate 13-hydroxylinoleic acid, a lipoxygenase product, which is significantly increased after LPS treatment of the cells, covalently bound to cellular constituents and may, therefore, be possibly involved in the formation of TNF.

Animals↗
PubMed2006

Therapeutic options for 5-lipoxygenase inhibitors.

5-Lipoxygenase (5-LO) catalyzes the conversion of arachidonic acid (AA) into leukotriene (LT) A(4) and 5-hydroperoxyeicosatetraenoic acid. LTA(4) can then be converted into LTB(4) by LTA(4) hydrolase or into LTC(4) by LTC(4) synthase and the LTC(4) synthase isoenzymes MGST2 and MGST3. LTB(4) is a potent chemoattractant for neutrophils, eosinophils and monocytes leading to adherence of phagocytes to vessel walls, neutrophil degranulation and release of superoxide anions. LTC(4) and its metabolite, LTD(4), are potent bronchoconstrictors that increase vascular permeability and stimulate mucus secretion from airways. Recent data also suggest that LT have an immunomodulatory role. Due to these properties, the increased biosynthesis of LT in asthma, and based upon clinical data obtained with CysLT(1) receptor antagonists in asthma patients, there is a consensus that CysLT play a prominent role in asthma. In this review, we summarize the knowledge on possible functions of the 5-LO pathway in various diseases like asthma, cancer and cardiovascular events and review the corresponding potential therapeutic roles of 5-LO inhibitors.

Animals↗
PubMed1986

Effects of a thromboxane synthetase inhibitor (OKY-046) and a lipoxygenase inhibitor (AA-861) on bronchial responsiveness to acetylcholine in asthmatic subjects.

The effect of a selective thromboxane synthetase inhibitor, OKY-046, and a selective 5-lipoxygenase inhibitor, AA-861, on bronchial responsiveness to acetylcholine was studied in 23 asthmatic subjects. The provocative concentration of acetylcholine producing a 20% fall in forced expiratory volume in one second (PC20 FEV1) was measured before and after oral administration of OKY-046 (3000 mg over four days) and AA-861 (1100 mg over four days) and inhalation of OKY-046 (30 mg) in 10, 10, and nine asthmatic subjects respectively. Baseline values of FEV1 and forced vital capacity (FVC) were not altered by oral OKY-046, oral AA-861, or inhaled OKY-046. The geometric mean value of PC20 FEV1 increased significantly from 0.55 to 2.24 mg/ml after oral OKY-046, but was unchanged after inhalation of OKY-046 and after oral administration of AA-861. These results suggest that thromboxane A2 may play a part in bronchial hyperresponsiveness to acetylcholine.

Acetylcholine↗
PubMed2006

Application of the ferrous oxidation-xylenol orange assay for the screening of 5-lipoxygenase inhibitors.

5-Lipoxygenase (5-LO) is the key enzyme involved in leukotriene synthesis and its improper regulation is implicated in several inflammatory diseases. A rapid and sensitive assay for 5-LO activity suitable for high-throughput format is not yet available. In this study, we examined whether the ferrous oxidation-xylenol orange (FOX) assay could be applicable for the high-throughput screening of 5-LO inhibitors. Using insect cell lysates overexpressing rat 5-LO, the effects of cofactors of 5-LO such as ATP, Ca2+, and L-alpha-phosphatidylcholine (PC) on the color development of FOX reagents were investigated. ATP quenched substantially color development by hydroperoxide, an intermediate of 5-LO reaction, and an optimum concentration of ATP with little interference was determined as 20 microM. Ethylenediaminetetraacetate (0.4 mM) also affected the complex formation with FOX reagents. On the other hand, neither Ca2+ nor PC influenced complex formation with FOX reagents. Under optimized assay conditions, zileuton, a 5-LO-specific inhibitor, exhibited inhibitory potency (IC50 values of 0.1-0.2 microM) similar to that determined by the conventional spectrophotometric assay. Taken together, this study shows that the FOX assay with some modifications can be employed for high-throughput assay format for the measurement of 5-LO activity at the stage of primary screening.

Animals↗
PubMed1993

5-Hydroxyanthranilic acid derivatives as potent 5-lipoxygenase inhibitors.

Three new 5-lipoxygenase inhibitors, designated as BU-4601 A, B and C, were found in the fermentation broth of Streptomyces sp. strain No. AA2807. Their structures were identified as isodecyl, isoundecyl and isolauryl esters of 5-hydroxyanthranilic acid, respectively. Based on their structures, five related esters were synthesized and evaluated for biological activity as inhibitors of 5-lipoxygenase. Both naturally-occurring and chemically-synthesized compounds exhibited almost equal levels of 5-lipoxygenase inhibitory activities in vitro.

Animals↗
PubMed1985

Interactions of a variety of lipoxygenase inhibitors with a supplementary binding site on soybean lipoxygenase.

Studies on the combined effects of a variety of lipoxygenase inhibitors and cyclo-oxygenase inhibitors revealed strong evidence for the existence of supplementary binding sites on lipoxygenases which modify the reactions of inhibitors with the catalytic site of the enzyme. Independent of their low or non-existent inhibitory reaction at the catalytic site, compounds which interact more effectively with this putative supplementary site are capable of blunting the inhibitory efficacy of potent lipoxygenase inhibitors. Although the degree of interaction with the catalytic site determines the potency of inhibitors, an additional reaction at the supplementary site is also obligatory for inhibitory efficacy. We found that potent lipoxygenase inhibitors possess high affinities for both sites, whereas weak inhibitors and suitable cyclo-oxygenase inhibitors interact predominantly with the supplementary site on the lipoxygenase and possess low or negligible affinities for its catalytic site.

Acetone↗