5-Lipoxygenase: A promising drug target against inflammatory diseases-biochemical and pharmacological regulation

Current Drug Targets

Volumn 15, Issue 4, 2014, Pages 410-422

  Anwar, Yasir ^a   Sabir, Jamal S M ^a   Qureshi, Muhammad I ^a   Saini, Kulvinder S ^a  

^a KING ABDULAZIZ UNIVERSITY   (Saudi Arabia)

Author keywords

5 Lipoxygenase; Cytokines; Leukotrienes; New drug discovery; Small molecules

Indexed keywords

1 [3 (4 BIPHENYLYLMETHYL) 4 HYDROXYCHROMAN 7 YL]CYCLOPENTANECARBOXYLIC ACID; 1,5 DIARYLPYRAZOLE; 3 O ACETYL 11 KETO BETA BOSWELLIC ACID; 5 ETHYL 2 HYDROXY 4 [6 METHYL 6 (1H TETRAZOL 5 YL)HEPTYLOXY]ACETOPHENONE; 5 LIPOXYGENASE ACTIVATION PROTEIN; 5 OXO ETE; ARACHIDONATE 5 LIPOXYGENASE; ATRELEUTON; BAYU 9773; CALCIUM CALMODULIN DEPENDENT PROTEIN KINASE KINASE; CALCIUM ION; CO ACTOSIN LIKE PROTEIN; CYCLIN DEPENDENT KINASE 1; DIARYL PRIMIDINE DERIVATIVE; DICER; FIBOFLAPON; HYPERFORIN; INDOLIZINE DERIVATIVE; LEUKOTRIENE RECEPTOR; LEUKOTRIENE RECEPTOR BLOCKING AGENT; LIPID HYDROPEROXIDE; MITOGEN ACTIVATED PROTEIN KINASE 1; MONTELUKAST; PEPTIDES AND PROTEINS; PF 4191834; PHOSPHATIDYLCHOLINE; PYRAZOLYLALKYL AMIDE; QUIFLAPON; RESOLVIN D1; SETILEUTON; SULFONAMIDE; THROMBOCYTE ACTIVATING FACTOR; TRANSFORMING GROWTH FACTOR BETA; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ASTHMA; DISEASE COURSE; DRUG EFFICACY; DRUG SAFETY; GENE EXPRESSION; HUMAN; HYDROPHOBICITY; INFLAMMATORY DISEASE; NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PROTEIN INTERACTION; PROTEIN PHOSPHORYLATION; REMISSION; REVIEW; RHEUMATOID ARTHRITIS; SIGNAL TRANSDUCTION;

ARACHIDONATE 5-LIPOXYGENASE; BIOLOGICAL MARKERS; DRUG DESIGN; HUMANS; INFLAMMATION; LIPOXYGENASE INHIBITORS; SIGNAL TRANSDUCTION;

EID: 84896337216     PISSN: 13894501     EISSN: 18735592     Source Type: Journal    
DOI: 10.2174/1389450114666131209110745     Document Type: Review

References (156)

1. Gaffney BJ. Lipoxygenases: Structural principles and Spectroscopy. Ann Review Biophys Biomol Struc 1996; 25: 431-59.
2. Kubo I, Masuoka N, Joung HT, Shimizu K, Nihei KI. Multifunctional Antioxidant Activities of Alkyl Gallates. The Open Bioact Comp J 2010; 3: 1-11.
3. Gilbert NC, Bartlett SG, Waight MT, et al. The Structure of Human 5-Lipoxygenase. Science 2011; 14: 217-19.
4. Funk CD. The molecular biology of mammalian lipoxygenases and the quest for eicosanoid functions using lipoxygenase deficient mice. Biochem Biophys Acta 1996; 1304: 65-84.
5. Silverman ES, Du J, Sanctis GTD, et al. Egr-1 and Sp1 Interact functionally with the 5-lipoxygenase promoter and its naturally occurring mutants. Am J Respir Cell Mol Biol 1998; 19: 316-23.
6. In KH, Asano K, Beier D, et al. Naturally occurring mutations in the human 5-lipoxygenase gene promoter that modify transcription factor binding and reporter gene transcription. J Clin Invest 1997; 99: 1130-7.
7. Luo M, Jones SM, Golden MP, Brock TG. Nuclear localization of 5-lipoxygenase as a determinant of LTB4 synthetic capacity. Proc Nat Acad Sci USA 2003; 100: 12165-70.
8. Murphy RC, Gijon MA. Biosynthesis and metabolism of leukotrienes. Biochem J 2007; 405: 379-95.
9. Peters-Golden M, Brock TG. 5-lipoxygenase and flap. Prostaglandins Leuktr Essent Fatty Acids 2003; 69: 99-109.
10. Samuelsson B, Dahlen SE, Lindgren JA, Rouger CA, Serhan CN. Leukotrienes and lipoxins structures, biosynthesis and biological effects. Science 2007; 237: 1171-6.
11. Golden MP, Henderson WR. Leukotrienes. N Engl J Med 2007; 357: 1841-54.
12. Yokomizo T, Izumi T, Chang K, Takuwa Y, Shimizu T. A Gprotein-coupled receptor for leukotriene B4 that mediates chemotaxis. Nature 1997; 367: 620-24.
13. Murphy RC, Hammarstrom S, Samuelsson B. Leukotriene C: a slow reacting substance from murine mastocytoma cells. Proc Natl Acad Sci USA 1979; 76: 4275-9.
14. Borgeat P, Samuelsson B. Metabolism of arachidonic acid in polymorphonuclear leukocytes. Structural analysis of novel hydroxylated compounds. J Biol Chem 1979; 254: 7865-69.
15. Borgeat P, Samuelsson B. Arachidonic acid metabolism in polymorphonuclear leukocytes: unstable intermediate in formation of dihydroxy acids. Proc Natl Acad Sci USA 1979; 76: 3213-7.
16. James AJ, Penrose JF, Cazaly AM, Holgate ST, Sampson AP. Human fibroblasts express the 5-lipoxygenase pathway. Respir Res 2006; 7: 1-11.
17. Zhang YY, Walker JL, Huang A, et al. Expression of 5-lipoxygenase in pulmonary artery endothelial cells. Biochem J 2002; 361: 267-76.
18. Dipersio JF, Billing P, Williams R, Gasson JC. Human granulocyte-macrophage colony-stimulating factor and other cytokines prime human neutrophils for enhanced arachidonic acid release and leukotriene B4 synthesis. J Immuno 1988; 140: 4315-22.
19. Dahinden CA, Zingg J, Maly FE, de Weck AL. Leukotriene production in human neutrophils primed by recombinant human granulocyte/ macrophage colony-stimulating factor and stimulated with the complement component C5A and FMLP as second signal. J Exp Med 1988; 167: 1282-95.
20. Schatz-Munding M, Ullrich V. Priming of human polymorphonuclear leukocytes with granulocyte-macrophage colony-stimulating factor involves protein kinase C rather than enhanced calcium mobilisation. Eur J Biochem 1992; 204: 705-12.
21. McDonald PP, Pouliot M, Borgeat P. Enhancement by GM-CSF of agonist-induced 5-lipoxygenase activation in human neutrophils involves protein synthesis and gene transcription. J Lipid Mediat 1993; 6: 59-67.
22. Surette ME, Palmantier R, Gosselin J, Borgeat P. Lipopolysaccharides prime whole human blood and isolated neutrophils for the increased synthesis of 5-lipoxygenase products by enhancing arachidonic acid availability: Involvement of the CD14 antigen. J Lipid Med 1993; 178: 1347-55.
23. Bozza PT, Payne JL, Goulet JL, Weller PF. Mechanisms of platelet-activating factor-induced lipid body formation: requisite roles for 5-lipoxygenase and de novo protein synthesis in the compartmentalization of neutrophil lipids. J Exp Med 1996; 183: 1515-25.
24. Surette ME, Dallaire N, Jean N, Picard S, Borgeat P. Mechanisms of the priming effect of lipopolysaccharides on the biosynthesis of leukotriene B4 in chemotactic peptide-stimulated human neutrophils. FASEB J 1998; 12: 1521-31.
25. Werz O. 5-Lipoxygenase: cellular biology and molecular pharmacology current drug targets. Inflamm Allergy 2002; 1: 23-44.
26. Ye Y, Lin Y, Perez-polo JR, et al. Phosphorylation of 5-lipoxygenase at Ser523 by protein kinase determines whether pioglitazone and atorvastatin induce proinflammatory leukotriene B4 or anti-inflammatory 15-EPi-Lipoxin a4 production. J Immunol 2008; 181: 3515-23.
27. Flamand N, Luo M, Golden MP, Brock TG. Phosphorylation of serine 271 on 5-lipoxygenase and its role in nuclear export. J Biol Chem 2009; 284: 306-18.
28. Takajo T, Tsuchida K, Ueno K, Koshiishi I. Feedback activation of ferrous 5-lipoxygenase during leukotriene synthesis by coexisting linoleic acid. J Lipid Res 2007; 48: 1371-7.
29. Werz O, Steinhilber D. Development of 5-lipoxygenase inhibitorslessons from cellular enzyme regulation. Biochem Pharmacol 2005; 70: 327-33.
30. Manev H, Uz T, Sugaya K, Qu T. Putative role of neuronal 5-lipoxygenase in an aging brain. FASEB J 2000; 14: 1464-9.
31. Radmark O, Samuelsson B. 5-Lipoxygenase: Regulation and possible involvement in atherosclerosis. Prostaglandins other Lipid Mediat 2007; 83: 162-74.
32. Luo M, Flamand N, Brock TG. Metabolism of arachidonic acid to eicosanoids within the nucleus. Biochim Biophys Acta 2006; 1761: 618-25.
33. Samuelsson B. Leukotrienes: mediators of immediate hypersensitivity reactions and inflammation. Science 1983; 220: 568-75.
34. Rouzer CA, Matsumoto T, Samuelsson B. Single protein from human leukocytes possesses 5-lipoxygenase and leukotriene A4 synthase activities. Proc Natl Acad Sci USA 1986; 83: 857-61.
35. Werz O, Steinhilber D. Pharmacological intervention with 5-lipoxygenase: new insights and novel compounds. Exp Opin Ther Patents 2005; 15: 505-19.
36. Radmark O. Arachidonate 5-lipoxygenase. Prostaglandins Other Lipid Mediat 2002; 68-69: 211-34.
37. Folco G, Murphy RC. Eicosanoid transcellular Biosynthesis: From cell-cell interactions to a vivo tissue Responses. Pharmacol Rev 2006; 58: 375-88.
38. Radmark O, Samuelsson B. Regulation of 5-lipoxygenase enzyme activity. Biochem Biophys Res Commun 2005; 338: 102-10.
39. Werz O, Steinhilber D. Therapeutic options for 5-lipoxygenase inhibitors. Pharmacol Ther 2006; 112: 701-18.
40. Penrose JF, Spector J, Baldasaro M, et al. Molecular cloning of the gene for human leukotriene C4 synthase organization, nucleotide sequence and chromosomal localization to 5q35. J Biol Chem 1996; 271: 11356-61.
41. Dixon RA, Diehl RE, Opas E, et al. Requirement of a 5-lipoxygenase activating protein for leukotriene synthesis. Nature 1990; 343: 282-84.
42. Bresell A, Weinander R, Lundqvist G, et al. Bioinformatics and enzymatic characterization of the MAPEG superfamily. FEBS J 2005; 272: 1688-03.
43. Woods JW, Evans JF, Ethier D, et al. 5-Lipoxygenase and 5-lipoxygenase-activating protein are localized in the nuclear envelope of activated human leukocytes. J Exp Med 1993; 178: 1935-46.
44. Strid T, Svartz J, Franck N, et al. Distinct parts of leukotriene C4 synthase interact with 5-lipoxygenase and 5-lipoxygenase activating protein. Biochem Biophys Res Commun 2009; 381: 518-22.
45. Plante H, Picard S, Mancini J, Borgeat P. 5-Lipoxygenaseactivating protein homodimer in human neutrophils: evidence for a role in leukotriene biosynthesis. Biochem J 2006; 393: 211-18.
46. Robert SB, Goulet LJ, Richard GJ, Beverly KH. Role of the 5-lipoxygenase-activating protein (FLAP) in murine acute inflammatory responses. J Exp Med 1997; 185: 1065-75.
47. Mandal AK, Jones PB, Bair AM, et al. The nuclear membrane organization of leukotriene synthesis. Proc Natl Acad Sci USA 2008; 105: 20434-39.
48. Oosterveer DM, Vermissen J, Yazdanpanah M, et al. 5-Lipoxygenase activating protein (ALOX5AP) gene variants associate with the presence of xanthomas in familial hypercholesterolemia. Atherosclerosis 2009; 206: 223-27.
49. Provost P, Samuelsson B, Radmark O. Interaction of 5-lipoxygenase with cellular proteins. Proc. Natl Acad Sci USA 1999; 96: 1881-85.
50. Liu L, Wei Z, Wang Y, Wan M, Cheng Z, Gong W. Crystal structure of human coactosin-like protein. J Mol Biol 2004; 344: 317-23.
51. Provost P, Doucet J, Hammarberg T, Gerisch G, Samuelsson B, Radmark O. 5-lipoxygenase interacts with coactosin-like protein. J Biol Chem 2001; 267: 16520-27.
52. Provost P, Doucet J, Stock A, Gerisch G, Samuelsson B, Radmark O. Coactosin-like protein, a human f-actin-binding protein: critical role of lysine-75. Biochem J 2001; 359: 255-63.
53. Burkert E, Radmark O, Samuelsson B, Steinhilber D, Werz O. Hypertonicity suppresses ionophore-induced product formation and translocation of 5-lipoxygenase in human leukocytes. J Leuko Bio 2002; 71: 477-86.
54. Rankonjac M, Fischer L, Provost P, et al. Coactosin-like protein supports 5-lipoxygenase enzyme activity and up-regulates leukotriene A4 production. Proc Natl Acad Sci USA 2006; 103: 13150-55.
55. Feisst C, Pergola C, Rakonjac M, et al. Hyperforin is a novel type of 5-lipoxygenase inhibitor with high efficacy in vivo. Cell Mol Life Sci 2009; 66: 2759-71.
56. Esser J, Rakonjac M, Hofmann B, et al. Coactosin-like protein functions as a stabilizing chaperone for 5-lipoxygenase: role of tryptophan 102. Biochem J 2009; 425: 265-74.
57. Pergola C, Dodt G, Rossi A, et al. Erk-mediated regulation of leukotriene biosynthesis by androgens: a molecular basis for gender differences in inflammation and asthma. Proc Natl Acad Sci USA 2008; 105: 19881-86.
58. Percival MD. Human 5-lipoxygenase contains an essential iron. J Biol Chem 1991; 266: 10058-61.
59. De Carolis E, Denis D, Riendeau D. Oxidative inactivation of 5-lipoxygenase in phosphatidylecholine vesicles. Eur J Biochem 1996; 235: 416-23.
60. Lepley RA, Muskardin DT, Fitzpatrick FA. Tyrosine kinase activity modulates catalysis and translocation of cellular 5-lipoxygenase. J Biol Chem 1996; 271: 6179-84.
61. Cantley LC, Auger KR, Carpenter C, et al. Oncogenes and signal transduction. Cell 1991; 64: 281-02.
62. Mayer BJ, Hamaguchi M, Hanafusa H. A novel viral oncogene with structural similarity to phospholipase C. Nature 1988; 332: 272-25.
63. Koch CA, Anderson D, Moran ME, Ellis C, Pawson T. SH2 and SH3 domains: elements that control interactions of cytoplasmic signaling proteins. Science 1991; 252: 668-74.
64. Lepley RA, Fitzpatrick FA. 5-Lipoxygenase contains a functional Src homology 3-binding motif that interacts with the Src homology 3 domain of grb2 and cytoskeleton protein. J Biol Chem 1994; 269: 24163-68.
65. Wurthner JU, Frank DB, Felici A, et al. Transforming growth factor-beta receptor-associated protein 1 is a smad4 chaperone. J Biol Chem 2001; 276: 19495-02.
66. Brungs M, Radmark O, Samuelsson B, Steinhilber D. Sequential induction of 5-lipoxygenase gene expression and activity in Mono Mac 6 cells by transforming growth factor beta and 1, 25-dihydroxyvitamin D-3. Proc Natl Acad Sci USA 1995; 92: 107-11.
67. Steinhilber D, Radmark O, Samuelsson B. Transforming growth factor-α upregulates 5-lipoxygenase activity during myeloid maturation. Proc Natl Acad Sci USA 1993; 90: 5984-8.
68. Zhang H, Kolb FA, Jaskiewicz L, Westhof E, Filipowicz W. Single processing center models for human dicer and bacterial RNase III. Cell 2004; 118: 57-68.
69. Zhang H, Kolb FA, Brondani V, Billy E, Filipowicz W. Human dicer preferentially cleaves dsRNAs at their termini without a requirement for ATP. EMBO J 2002; 21: 5875-85.
70. Renqvist VD, Pepin G, Rakonjac M, et al. Human dicer c-terminus functions as a 5-lipoxygenase binding domain. Biochem Biophys Acta 2009; 1789: 99-08.
71. 2+activates 5-lipoxygenase in vitro: dependency on concentrations of phosphatidylcholine and arachidonic acid. Biochemistry 2000; 39: 1840-48.
72. Pande AH, Moe D, Nemec KN, Qin S, Tan S, Tatulian SA. Modulation of human 5-lipoxygenase activity by membrane lipids. Biochemistry 2004; 43: 14653-66.
73. Pande AH, Qin S, Tatulian SA. Membrane fluidity is a key modulator of membrane binding, insertion, and activity of 5-lipoxygenase. Biophys J 2005; 88: 4084-94.
74. Hornig C, Albert D, Fischer L, Hornig M, Radmark O, Steinhilber D, Werz O. 1-Oleoyl-2-acetylglycerol stimulates 5-lipoxygenase activity via a putative (Phospho) lipid-binding site within the Nterminal C2-like domain. J Biol Chem 2005; 280: 26913-21.
75. Zagryagskaya AN, Aleksandrov DA, Pushkareva MA, Galkina SI, Grishina ZV, Sudina GF. Biosynthesis of leukotriene B4 in human polymorphonuclear leukocytes: regulation by cholesterol and other lipids. J Immunotox 2008; 5: 347-52.
76. Zou Y, Kim D, Jung KJ, et al. Lysophosphatidylcholine enhances oxidative stress via the 5-lipoxygenase pathway in rat aorta during aging. Rejuvenation Res 2009; 12: 15-24.
77. Schatz MM, Hatzelmann A, Ullrich V. The involvement of extracellular calcium in the formation of 5-lipoxygenase metabolites by human polymorphonuclear leukocytes. Eur J Biochem 1991; 197: 487-93.
78. Hammarberg T, Radmark O. 5-lipoxygenase binds calcium. Biochemistry 1999; 38: 4441-47.
79. Bindu PH, Sastry GM, Sastry GN. Characterization of calcium and magnesium binding domains of human 5-lipoxygenase. Biochem Biophys Res Commun 2004; 320: 461-67.
80. Franke L, Schwarz O, Kuhrt LM, et al. Identification of naturalproduct-derived inhibitors of 5-lipoxygenase activity by ligandbased virtual screening. J Med Chem 2007; 50: 2640-46.
81. Noguchi M, Miyano M, Matsumoto T. Physicochemical characterization of ATP binding to human 5-lipoxygenase. Lipids 1996; 31: 367-71.
82. Hammarberg T, Provost P, Persson B, Radmark O. The N-terminal domain of 5-lipoxygenase binds calcium and mediates calcium stimulation of enzyme activity. J Biol Chem 2000; 275: 38787-93.
83. 2+independent phospholipase A2 and 5-lipoxygenase in macrophages. Prostaglandin Lipid Mediat 2009; 88: 51-61.
84. Werz O, Szellas D, Steinhilber D. Reactive oxygen species released from granulocytes stimulate 5-lipoxygenase activity in a Blymphocytic cell line. Eur J Biochem 2000; 267: 1263-69.
85. Chen XS, Funk CD. The N-terminal "Barrel" domain of 5-lipoxygenase is essential for nuclear membrane translocation. J Biol Chem 2001; 276: 811-18.
86. Werz O, Klemm J, Radmark O, Samuelsson B. P38 MAP kinase mediates stress-induced leukotriene synthesis in a human Blymphocyte cell line. J Leuk Biol 2001; 70: 830-38.
87. Imai H, Narashima K, Arai M, Sakamoto H, Chiba N, Nakagawa Y. Suppression of leukotriene formation in RBL-2H3 cells that overexpressed phospholipid hydroperoxide glutathione peroxidase. J Biol Chem 1998; 273: 1990-97.
88. Radmark O, Werz O, Steinhilber D, Samuelsson B. 5-Lipoxygenase: regulation of expression and enzyme activity. Trends in Biochem Sci 2007; 32: 332-41.
89. Tokuko T, Kazunori T, Koichi U, Ichiro K. Feedback activation of ferrous 5-lipoxygenase during leukotriene synthesis by coexisting linoleic acid. J Lip Res 2007; 48: 1371-7.
90. Joost P, Methner A. Phylogenetic analysis of 277 human Gprotein-coupled receptors as a tool for the prediction of orphan receptor ligands. Genome Biol 2002; 3: R0063.1-16.
91. Patel P, Cossette C, Anumolu JR, et al. Structural requirements for activation of the 5-oxo-6E, 8Z, 11Z, 14Z-eicosatetraenoic acid (5-oxo-ETE) receptor: identification of a mead acid metabolite with potent agonist activity. J Pharmacol Exp Ther 2008; 325: 698-07.
92. Krishnamoorthy S, Recchiuti A, Chiang N, et al. Resolvin D1 binds human phagocytes with evidence for proresolving receptors. Proc Natl Acad Sci USA 2010; 107: 1660-5.
93. Richard RN, Michael S, Terry K, Arthur C. International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification. XXXVIII. Update on Terms and Symbols in Quantitative Pharmacology. Pharmacol Rev 2003; 55: 597-06.
94. Rovati GE, Capra V, Nicosia S. More on the classification of cysteinyl leukotriene receptors. Trends Pharmacol Sci 1997; 18: 148-49.
95. Back M. Functional characteristics of cysteinyl-leukotriene receptor subtypes. Life Sci 2002; 71: 611-22.
96. Norel X, Brink C. The quest for new cysteinyl-leukotriene and lipoxin receptors: recent clues. Pharmacol Ther 2003; 103: 81-94.
97. Rovati GE, Capra V. Cysteinyl-leukotriene receptors and cellular signals. Sci World J 2007; 7: 1375-92.
98. Austen KF, Maekawa A, Kanaoka Y, Boyce JA. The leukotriene E4 puzzle: finding the missing pieces and revealing the pathobiologic implications. J Allergy Clin Immunol 2009; 124: 406-14.
99. Arita M, Ohira T, Sun YP, Elangovan S, Chiang N, Serhan CN. Resolvin E1 selectively interacts with leukotriene B4 receptor BLT1 and ChemR23 to regulate inflammation. J Immunol 2007; 178: 3912-17.
100. Okuno T, Iizuka Y, Okazaki H, Yokomizo T, Taguchi R, Shimizu T. 12(S)-Hydroxyheptadeca-5Z,8E,10E-trienoic acid is a natural ligand for leukotriene B4 receptor 2. J Exp Med 2008; 205: 759-66.
101. Paruchuri S, Tashimo H, Feng C, et al. Leukotriene E4-induced pulmonary inflammation is mediated by the P2Y12 receptor. J Exp Med 2009; 206: 2543-55.
102. Fredman G, Van Dyke TE, Serhan CN. Resolvin E1 regulates adenosine diphosphate activation of human platelets. Arterioscler Thromb Vasc Biol 2010; 30: 2005-13.
103. Lee SR, Carlos H. Serezani, Medeiros, Ballinger MN, Golden MP. Crosstalk between Prostaglandin E2 and Leukotriene B4 Regulates Phagocytosis in Alveolar Macrophages via Combinatorial Effects on Cyclic AMP. J Immunol 2009; 182: 530-37.
104. Hoffman B, Steinhilber D. 5-Lipoxygenase inhibitors: a review of recent patents. (2010-2012). Expert Opin Ther Patents 2013; 23: 1-14.
105. Tantisira KG, Lima J. Lima, Sylvia J, Klanderman B, Weiss ST. 5-lipoxygenase Pharmacogenetics in Asthma: Overlap with CystLTR1 Loci. Pharmagenet Genomic 2009; 19: 244-47.
106. Poeckel D, Funk CD. The 5-lipoxygenase/leukotriene pathway in preclinical models of cardiovascular disease. Cardiovas Res 2010; 86: 243-53.
107. Bernstein JA, Liu N, Knorr BA, Smugar SS, Hanley WD, Reiss TF, Greenberg S. MK-0633, a potent 5-lipoxygenase inhibitor, in chronic obstructive pulmonary disease. Respir Med 2011; 105: 392-01.
108. Sarveswaran S, Thamilselvan V, Brodie C, Ghosh J. Inhibition of 5-lipoxygenase triggers apoptosis in prostate cancer cells via downregulation of protein kinase C-epsilon. Biochim Biophys Acta 2011: 1813; 2108-17.
109. Musiyenko A, Correa L, Stock N, et al. A Novel 5-Lipoxygenase-Activating Protein Inhibitor, M679, Reduces Inflammation in the Respiratory Syncytial Virus-Infected Mouse Eye. Clin Vac Immun 2009: 16; 1654-59.
110. Tristão FS, Rocha FA, Moreira AP, Cunha FQ, Rossi MA, Silva JS. 5-lipoxygenase activity increases susceptibility to Paracoccidioides brasiliensis experimental infection. Infect Immun 2013; 81: 1256-66.
111. Tsuji F, Aono H, Tsuboi T, et al. Role of Leukotriene B4 in 5-Lipoxygenase Metabolite-and Allergy Induced Itch-Associated Responses in Mice. Biol Pharm Bull 2010; 33: 1050-3.
112. Chu J, Pratico D. Involvement of 5-lipoxygenase activating protein in the amyloidotic phenotype of an Alzheimer's disease mouse model. J Neuroinflamm 2012; 9: 1-17.
113. Manev H, Chen H, Dzitoyeva S, Manev R. Cyclooxygenases and 5-lipoxygenase in Alzheimer's disease. Prog in Neuro-Psychopharm Biolog Psychia 2011; 35: 315-19.
114. Russell FD, Windegger T, Hamilton KD, Cheetham NWH. Effect of the novel wound healing agent, OPAL A on leukotriene B4 production in human neutrophils and 5-lipoxygenase activity. Wound Pract Res J Aus Wound Manag Assoc 2011; 19: 200-3.
115. Showell HJ, Pettipher ER, Cheng JB, et al. The in vitro and in vivo pharmacologic activity of the potent and selective leukotriene B4 receptor antagonist CP-105696. J Pharmacol Exp Ther 1995; 273: 176-84.
116. Herron DK, Goodson T, Bollinger NG, et al. Leukotriene B4 receptor antagonists: the LY255283 series of hydroxyacetophenones. J Med Chem 1995; 35: 1818-28.
117. Tudhope SR, Cuthbert NJ, Abram TS, et al. BAYu9773, a novel antagonist of cysteinyl-leukotrienes with activity against two receptor subtypes. Eur J Pharmacol 1994; 264: 317-23.
118. Grant GE, Rokach J, Powell WS. 5-Oxo-ETE and the OXE receptor. Pros Lipid Med 2009; 89: 98-04.
119. Mamedova L, Capra V, Accomazzo MR, et al. CysLT1 leukotriene receptor antagonists inhibit the effects of nucleotides acting at P2Y receptors. Biochem Pharmacol 2005; 71: 115-25.
120. Dastidar SG, Dawange MB, Ghorpade SM, et al. 5-lipoxygenase inhibitors. WO2012014127, February 2, 2012.
121. Liu H, Jiang H, Zhou Y, et al. 5-lipoxygenase inhibitor and preparation method, medical composite and application thereof. CN101684098, March 31, 2010.
122. Gokaraju GR, Gokaraju RR, Golakoti T, Gottumukkala VS, Sengupta K. Analogs of 3-o-acetyl-11-keto-beta-boswellic acid. US20120035176, February9, 2012.
123. Verma AK, Malhotra S, Marimganti S, et al. 5-lipoxygenase inhibitors. WO2011161615, December 29, 2011.
124. Lui H, Jiang H, Yu Z, et al. Novel pyrazole 5-lipoxygenase small molecule inhibitors, preparation method, pharmaceutical composition and application thereof. CN101544631, September 30, 2009.
125. Bosanac T, Stephane DL, Lo HY, Nemoto PA, Olague A. Indolizine inhibitors of leukotriene production. WO2010027762, March 11, 2010.
126. Albert D, Zündorf I, Dingermann T, Müller WE, Steinhilber D, Werz O. "Hyperforin is a dual inhibitor of cyclooxygenase-1 and 5-lipoxygenase". Biochem Pharmacol 2002; 64: 1767-75.
127. Davidson EM, Rae SA, Smith MJ. Leukotriene B4, a mediator of inflammation present in synovial fluid in rheumatoid arthritis. Ann Rheum Dis 1983; 42: 677-9.
128. Blackburn WD Jr, Heck LW, Loose LD, Eskra JD, Carty TJ. Inhibition of 5-lipoxygenase product formation and polymorphonuclear cell degranulation by tenidap sodium in patients with rheumatoid arthritis. Arthritis Rheum 1991; 34: 204-10.
129. Griffiths RJ, Smith MA, Roach ML, et al. Collagen-induced arthritis is reduced in 5-lipoxygenase-activating protein-deficient mice. J Exp Med 1997; 185: 1123-9.
130. Griffiths RJ, Pettipher ER, Koch K, et al. Leukotriene B4 plays a critical role in the progression of collagen-induced arthritis. Proc Natl Acad Sci USA 1995; 92: 517-21.
131. Chou RC, Kim ND, Sadik CD, et al. Lipid-cytokine-chemokine cascade drives neutrophil recruitment in a murine model of inflammatory arthritis. Immunity 2010; 33: 266-78.
132. Mathis SP, Jala VR, Lee DM, Haribabu B. Nonredundant roles for leukotriene B4 receptors BLT1 and BLT2 in inflammatory arthritis. J Immunol 2010; 185: 3049-56.
133. Kim ND, Chou RC, Seung E, Tager AM, Luster AD. A unique requirement for the leukotriene B4 receptor BLT1 for neutrophil recruitment in inflammatory arthritis. J Exp Med 2006; 203: 829-35.
134. Chen M, Lam BK, Luster AD, et al. Joint tissues amplify inflammation and alter their invasive behavior via leukotriene B4 in experimental inflammatory arthritis. J Immunol 2010; 185: 5503-11.
135. Burnett BP, Jia Q, Zhao Y, Levy RM. A medicinal extract of Scutellaria baicalensis and Acacia catechu acts as a dual inhibitor of cyclooxygenase and 5-lipoxygenase to reduce inflammation. J Med Food 2007; 10: 442-51.
136. Levy RM, Khokhlov A, Kopenkin S, et al. Efficacy and safety of flavocoxid, a novel therapeutic, compared with naproxen: a randomized multicenter controlled trial in subjects with osteoarthritis of the knee. Adv Ther 2010; 27: 731-42.
137. Alvaro-Gracia JM. Licofelone-clinical update on a novel LOX/ COX inhibitor for the treatment of osteoarthritis. Rheumatology (Oxford) 2004; 43(Suppl. 1): i21-5.
138. Kulkarni SK, Singh VP. Licofelone: the answer to unmet needs in osteoarthritis therapy? Curr Rheumatol Rep 2008; 10: 43-8.
139. Berger W, De Chandt MT, Cairns CB. Zileuton: clinical implications of 5-Lipoxygenaseinhibition in severe airway disease. Int J Clin Pract 2007; 61: 663-76.
140. Bai C, Yu X, Yun R, et al. Association of 5-lipoxygenase gene polymorphisms with bronchial asthma. Exp Ther Med 2012; 4: 967-71.
141. Montuschi P, Peters-Golden ML. Leukotriene modifiers for asthma treatment. Clin Exp Allergy 2010; 40: 1732-41.
142. Drazen JM, Israel E, O'Byrne PM. Treatment of asthma with drugs modifying the leukotriene pathway. N Engl J Med 1999; 340: 197-06.
143. Joshi EM, Heasley BH, Macdonald TL. 2-ABT-S-oxide detoxification by glutathione S-transferases A1-1, M1-1 and P1-1: implications for toxicity associated with zileuton. Xenobiotica 2009; 39: 197-04.
144. Braeckman RA, Granneman GR, Locke CS, Machinist JM, Cavannaugh JH, Awni WM. The pharmacokinetics of zileuton in healthy young and elderly volunteers. Clin Pharmacokinet 1995; 29: 42-8.
145. Steinhilber D, Hofmann B. Recent Advances in the Search for Novel 5-Lipoxygenase Inhibitors. Basic Clin Pharmacol Toxicol 2014; 114(1): 70-7.
146. Amlani S, Nadarajah T, McIvor RA. Montelukast for the treatment of asthma in the adult population. Expert Opin Pharmacother 2011; 14: 2119-28.
147. Tardif JC, L'allier PL, Ibrahim R, et al. Treatment with 5-lipoxygenase inhibitor VIA-2291 (Atreleuton) in patients with recent acute coronary syndrome. Circ Cardiovasc Imaging 2010; 3: 298-07.
148. Ducharme Y, Blouin M, Brideau C, et al. The discovery of setileuton, a potent and selective 5-lipoxygenase inhibitor. ACS Med Chem Lett 2010; 1: 170-4.
149. Wasfi YS, Villarán C, de Tilleghem Cle B, et al. The efficacy and tolerability of MK-0633, a 5-lipoxygenase inhibitor, in chronic asthma. Respir Med 2012; 106: 34-46.
150. Bernstein JA, Liu N, Knorr BA, et al. MK-0633, a potent 5-lipoxygenase inhibitor, in chronic obstructive pulmonary disease. Respir Med 2011; 105: 392-01.
151. Masferrer JL, Zweifel BS, Hardy M, et al. Pharmacology of PF-4191834, a novel, selective non-redox 5-lipoxygenase inhibitor effective in inflammation and pain. J Pharmacol Exp Ther 2010; 334: 294-301.
152. Cortes-Burgos LA, Zweifel BS, Settle SL, et al. CJ-13610, an orally active inhibitor of 5-lipoxygenase is efficacious in preclinical models of pain. Eur J Pharmacol 2009; 617: 59-67.
153. Stock NS, Bain G, Zunic J, et al. 5-Lipoxygenase-activating protein (FLAP) inhibitors. Part 4: development Of 3-[3-tertbutylsulfanyl-1-[4-(6-ethoxypyridin-3-yl)benzyl]-5-(5-methylpyridin-2-y lmethoxy)-1H-indol-2-yl]-2, 2-dimethylpropionic acid (AM803), a potent, oral, once daily FLAP inhibitor. J Med Chem 2011; 54: 8013-29.
154. Bain G, King CD, Rewolinski M, et al. Pharmacodynamics and pharmacokinetics of AM103, a novel inhibitor of 5-lipoxygenaseactivating protein (FLAP). Clin Pharmacol Ther 2010; 87: 437-44.
155. Bora RS, Gupta D, Mukkur TKS, Saini KS. RNAi therapeutics for cancer: Challenges and Opportunities. Mol Med Reports 2012; 6: 9-15.
156. Sabir JSM, Abu-Zinadah OA, Bora RS, Ahmed MMM, Saini KS. Role of Toxicogenomics in the Development of Safe, Efficacious and Novel Anti-microbial Therapies. Infect Disord Drug Targets 2013; 13: 206-14.