Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rat basophilic leukemia cells exhibit 12-lipoxygenase activity only upon cell disruption. 12-Lipoxygenase may also possess 15-lipoxygenase activity, as is indicated by the formation of low amounts of 15(S)-HETE, in addition to the predominant product 12(S)-HETE, upon incubation of partially purified 12-lipoxygenase with arachidonic acid. With 5(S)-HPETE as substrate not only 5(S), 12(S)-diHETE and 5(S), 15(S)-diHETE are formed, but also LTA4, as was indicated by the presence of LTA4-derived LTB4-isomers. 12-Lipoxygenase from rat basophilic leukemia cells has many features in common with 12-lipoxygenase from bovine leukocytes. As was suggested for the latter enzyme, 12-lipoxygenase from rat basophilic leukemia cells may represent the remaining LTA4-synthase activity of 5-lipoxygenase, of which the 5-dioxygenase activity has disappeared upon cell disruption. Such a possible shift from 5-lipoxygenase activity to 12-lipoxygenase activity could not simply be induced by interaction of cytosolic 5-lipoxygenase with a membrane fraction after cell disruption, but may involve release of membrane-associated 5-lipoxygenase upon disruption of activated rat basophilic leukemia cells.
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PMID:12-Lipoxygenase from rat basophilic leukemia cells, an oxygenase with leukotriene A4-synthase activity. 139 Aug 74

Zileuton [N-(1-benzo[b]thien-2-ylethyl)-N-hydroxyure] inhibited 5-hydroxyeicosatetraenoic acid synthesis by rat basophilic leukemia cell 20,000 x g supernatant and rat polymorphonuclear leukocytes (PMNL) (IC50 = 0.5 and 0.3 microM) respectively. It also inhibited leukotriene (LT)B4 biosynthesis by rat PMNL (IC50 = 0.4 microM), human PMNL (IC50 = 0.4 microM) and human whole blood (IC50 = 0.9 microM). Inhibition of human PMNL LTB4 biosynthesis was removed readily by a simple wash procedure. At concentrations up to 100 microM, the compound produced little or no inhibition of several related enzymes, such as platelet 12-lipoxygenase, soybean and rabbit reticulocyte 15-lipoxygenase and sheep seminal vesicle cyclooxygenase. At p.o. doses from 0.5 to 5 mg/kg in the dog, zileuton produced a rapid and sustained inhibition of ex vivo blood LTB4 biosynthesis which correlated with the pharmacokinetic behavior of the compound. In a similar ex vivo study in the rat, the compound displayed an p.o. ED50 of 2 mg/kg. Zileuton was highly effective in preventing 6-sulfidopeptide LT formation in the rat peritoneal cavity triggered by an antigen-antibody reaction with an ED50 of 3 mg/kg. In experimental models of inflammation, zileuton significantly reduced arachidonic-acid induced mouse ear edema (ED50 = 31 mg/kg) and also attenuated inflammatory cell accumulation in the rat pleural Arthus reaction. The effectiveness of this compound for preventing LT formation in vitro, ex vivo and in vivo suggests its utility for preventing the pathophysiological effects of the LTs and other 5-lipoxygenase products in animals and in humans.
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PMID:5-lipoxygenase inhibitory activity of zileuton. 184 34

12-Lipoxygenase from rat basophilic leukemia cells was purified about 300-fold by protein-HPLC in a single run. Maximal 12-lipoxygenase activity was observed at pH 7.5, while the enzyme became almost inactive at pH 6 and 9. Although Ca2+ was not essential for 12-lipoxygenase activity, the partially purified enzyme was stimulated approx. 2-fold in the presence of 0.1-5.0 mM Ca2+. Contrary to 5-lipoxygenase from RBL-1 cells, 12-lipoxygenase was not inactivated by preincubation with Ca2+ for 1-10 min, nor was it stimulated by 0.1-10 mM ATP.
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PMID:Improved purification of 12-lipoxygenase from rat basophilic leukemia cells and conditions for optimal enzyme activity. 188 56

12-Lipoxygenase and 5-lipoxygenase from rat basophilic leukemia cells were separated by protein-HPLC in a single step. Upon incubation in the presence of Ca2+, 12-lipoxygenase converted arachidonic acid into 12(S)-hydroxyeicosatetraenoic acid and linoleic acid into 13(S)-hydro(pero)xyoctadecadienoic acid. The reaction products were analyzed by reversed-phase and chiral straight-phase HPLC with ultraviolet-detection. Using the cytosolic fraction of rat basophilic leukemia cells, optimal 12-lipoxygenase activity was observed at 10 degrees C. At 37 degrees C 12-lipoxygenase was very rapidly inactivated by its own product, hydroperoxy fatty acid, at low concentrations (10-100 nM).
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PMID:12-Lipoxygenase from rat basophilic leukemia cells: separation from 5-lipoxygenase and temperature-dependent inactivation by hydroperoxy fatty acid. 190 Feb 4

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.
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PMID:Studies on lipoxygenase inhibitors. I. MY3-469 (3-methoxytropolone), a potent and selective inhibitor of 12-lipoxygenase, produced by Streptoverticillium hadanonense KY11449. 308 66

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.
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PMID: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. 309 34

A cell-free human polymorphonuclear leukocyte preparation containing both 15- and 5-lipoxygenase activities was found to oxygenate phosphatidylcholine at carbon-15 of the arachidonic acid moiety. No oxygenation at carbon-5 was found. Under similar incubation conditions, soybean and rabbit reticulocyte 15-lipoxygenases also oxygenated phosphatidylcholine, whereas rat basophilic leukemia cell 5-lipoxygenase, rabbit platelet 12-lipoxygenase and rat liver cytochrome P-450 preparations did not. Our results suggest that the oxygenation of phospholipids may be a unique property of the 15-lipoxygenases.
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PMID:Oxygenation of phosphatidylcholine by human polymorphonuclear leukocyte 15-lipoxygenase. 392 6

We have confirmed previous observations that HL60 cells treated with a combination of 10 nM retinoic acid (RA), and 30 ng/ml granulocyte colony-stimulating factor (G-CSF) differentiate efficiently towards neutrophils, as characterized by their growth arrest and acquisition of phagocytic ability. Such low concentrations of RA alone provoked only a small proportion of HL60 cells to differentiate, and G-CSF alone provoked no differentiation. In the presence of 30 microM indomethacin (an inhibitor of the enzyme cyclooxygenase that catalyses the first step of prostanoid synthesis), the onset of differentiation provoked by RA plus G-CSF was more rapid, but the final proportion of mature cells was unchanged. Indomethacin also potentiated the growth arrest and differentiation of cells in response to 10 nM RA alone. Although the potentiating effect of indomethacin on RA-induced differentiation occurred at several indomethacin and RA concentrations, it was only apparent when the RA concentration used was alone sufficient to induce a small proportion of cells to differentiate. Indomethacin shifted the G-CSF dose-response curve of cells treated with 10 nM RA to lower G-CSF concentrations. 1 alpha,25-dihydroxy vitamin D3 (VitD3) induces HL60 cells to differentiate to monocytes and indomethacin also potentiated the differentiation of HL60 cells in response to low doses of VitD3 5,8,11-eicosatriynoic acid, an inhibitor of 5-lipoxygenase and 12-lipoxygenase, neither potentiated neutrophil differentiation of HL60 cells, nor prevented indomethacin potentiation of the differentiation of RA-primed cells. Treatment of cells with dexamethasone, a steroid whose effects include inhibition of arachidonate mobilization by phospholipase A2, potentiated RA-primed neutrophil differentiation in a manner similar to indomethacin. These observations suggest that an arachidonate metabolite formed downstream of cyclooxygenase suppresses differentiation of HL60 cells both to neutrophils and monocytes, probably by inhibiting some event essential to commitment to differentiation.
Leukemia 1994 Apr
PMID:Indomethacin potentiates the induction of HL60 differentiation to neutrophils, by retinoic acid and granulocyte colony-stimulating factor, and to monocytes, by vitamin D3. 751 72

Recently we demonstrated that Lewis lung (3LL) tumor cells express 12-lipoxygenase (12-LOX) mRNA and protein, respectively. In this study we partially sequenced the 12-LOX cDNA after reverse-transcription polymerase chain reaction amplification of 12-LOX mRNA from cultured 3LL cells. Comparison with platelet and leukocyte 12-LOX indicates that 3LL 12-LOX is identical with the platelet-type enzyme at least within the sequenced region. Further, we investigated the intracellular distribution of both 12-LOX enzyme protein and its activity which are prerequisites for understanding 12-LOX regulation. 12-LOX activity was monitored via the production of 12-hyroxyeicosatetraenoic acid from 3LL cells and their subcellular fractions using reverse-phase high performance liquid chromatography. 12-LOX protein was measured by direct slot blot and by Western Blotting. In 3LL cells, both 12-LOX activity and 12-LOX protein were predominantly localized in the cytosol. This 12-LOX activity was optimal at 37 degrees C. However at 24 degrees C and 10 degrees C, it showed 87% and 61% of this activity, respectively, thus differing distinctly from 12-LOX in platelets or rat basophilic leukemia cells. Incubation of 3LL cell homogenates with 0-100 microM free Ca2+ and subsequent separate analyses of cytosol and membrane fractions indicated that, as in platelets, an increase in intracellular free Ca2+ caused a loss of cytosolic 12-LOX activity. However, no significant Ca(2+)-induced increase in membrane-associated 12-LOX activity was observed under these conditions in 3LL cells. In contrast, at the 12-LOX protein level we observed a Ca(2+)-dependent loss in the cytosol and a concomitant increase in the membrane fraction. Thus, we suggest that 12-LOX in 3LL cells undergoes rapid translocation from cytosol to membrane in a Ca(2+)-dependent manner, but is no longer active or becomes inactivated at the membrane site.
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PMID:12-Lipoxygenase in Lewis lung carcinoma cells: molecular identity, intracellular distribution of activity and protein, and Ca(2+)-dependent translocation from cytosol to membranes. 779 91

5-Lipoxygenase has been recognized to be an important enzyme that catalyzes the first step in leukotriene production. In this study we examine whether or not phospholipids containing docosahexaenoic acid (DHA) affect 5-lipoxygenase activity of a rat basophilic leukemia cell line (RBL-1). Among the synthesized phospholipids examined, 1-oleoyl-2-docosahexaenoyl-sn-glycero-3-phosphocholine (1-oleoyl-2-DHA-PC) was found to be the most potent inhibitor of 5-lipoxygenase. The inhibition was dose-dependent and the ID50 value was 4.0 microM. When the fatty acid at the sn-2-position was replaced by other unsaturated fatty acids, the inhibitory activity decreased with decreasing numbers of both carbon atoms and double bonds in the fatty acids. Substitution at the 1-position of the DHA-containing PC also affected the inhibitory potency. If oleic acid was substituted with palmitic acid, the inhibition activity was completely abolished. Lineweaver-Burk plot analysis showed that the inhibition of 5-lipoxygenase by 1-oleoyl-2-DHA-PC was non-competitive. The inhibition by this synthesized phospholipid was very specific to 5-lipoxygenase; that is, it did not extend to fatty acid cyclooxygenase, 12-lipoxygenase or 15-lipoxygenase. These results suggest that endogenously existing DHA-containing phospholipids may affect 5-lipoxygenase activity and thus control leukotriene biosynthesis in vivo.
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PMID:Inhibitory effect of docosahexaenoic acid-containing phospholipids on 5-lipoxygenase in rat basophilic leukemia cells. 830 21


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