Skip to main content

Advertisement

Log in

Hepoxilins in cancer and inflammation—use of hepoxilin antagonists

  • Published:
Cancer and Metastasis Reviews Aims and scope Submit manuscript

Abstract

Cancer is often accompanied with inflammatory, thrombotic, and diabetic complications. Alternatively, chronic inflammation is believed to be a causative factor in several cancers. This review article brings together reported biological actions in these areas of the unstable naturally derived hepoxilins (HX), metabolites of arachidonic acid formed through the 12-LO pathway, and those of their synthetically derived stable HX antagonists (PBT; proprietary bioactive therapeutics). Although the HX pathway has been known for some three decades since its discovery by the author with much data originating from the author’s laboratory, studies by others over the past few years have confirmed early findings of the actions of HX as potent pro-inflammatory chemoattractant mediators and further showed HX to be involved in bacterial infection (Salmonella-induced intestinal inflammation and in bone inflammation caused by infection with the Lyme bacterium). The HX pathway appears to be an important early signal leading to inflammation. This provides important therapeutic potential for the PBTs as the only available selective antagonists of this pathway. The PBTs have shown benefit and efficacy in animal models of cancer and inflammation, which together with their known actions as anti-thrombotic (thromboxane (TPα) receptor antagonists) and hypoglycemic agents in vivo appears to make the PBTs suitable as therapeutics to control these disorders. The PBT structure is both stable in vivo and is essentially devoid of side effects in the animal models tested. The PBT structure serves as an important platform for selective HX and TX antagonists.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Scheme 1
Scheme 2
Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Pace-Asciak, C. R. (2009). The hepoxilins and their analogs—a review of their biology. British Journal of Pharmacology, 158, 972–981.

    Article  PubMed  CAS  Google Scholar 

  2. Blaho, V. A., Buczynski, M. W., Brown, C. R., & Dennis, E. A. (2009). Lipidomic analysis of dynamic eicosanoid responses during the induction and resolution of lyme arthritis. Journal of Biological Chemistry, 284, 21599–21612.

    Article  PubMed  CAS  Google Scholar 

  3. Dho, S., Grinstein, S., Corey, E. J., Su, W. G., & Pace-Asciak, C. R. (1990). Hepoxilin A3 induces changes in cytosolic calcium, intracellular pH and membrane potential in human neutrophils. Biochemical Journal, 266, 63–68.

    PubMed  CAS  Google Scholar 

  4. Sutherland, M., Schewe, T., & Nigam, S. (2000). Biological actions of the free acid of hepoxilin A3 on human neutrophils. Biochemical Pharmacology, 59, 435–440.

    Article  PubMed  CAS  Google Scholar 

  5. Mrsny, R. J., Gewirtz, A. T., Siccardi, D., Savidge, T., Hurley, B. P., Madara, J. L., et al. (2004). Identification of hepoxilin A3 in inflammatory events: a required role in neutrophil migration across intestinal epithelia. PNAS, 101, 7421–7426.

    Article  PubMed  CAS  Google Scholar 

  6. Demin, P. M., & Pace-Asciak, C. R. (1993). Synthesis of racemic 11,12-cyclopropyl analogs of hepoxilins A3 and B3. Tetrahedron Letters, 34, 4305–4308.

    Article  CAS  Google Scholar 

  7. Tilia, E., Michaillea, J.-J., Wernickea, D., Aldera, H., Costineana, S., Voliniaa, S., et al. (2011). Mutator activity induced by microRNA-155 (miR-155) links inflammation and cancer. PNAS, 108, 4908–4913.

    Article  Google Scholar 

  8. Pace-Asciak, C. R. (1993). Hepoxilins. General Pharmacology, 24, 805–810.

    PubMed  CAS  Google Scholar 

  9. Pace-Asciak, C. R. (1994). Hepoxilins: a review on their cellular actions. Biochimica et Biophysica Acta, 1215, 1–8.

    PubMed  CAS  Google Scholar 

  10. Pace-Asciak, C. R., Reynaud, D., & Demin, P. M. (1993). Enzymatic formation of hepoxilin A3 and B3. Biochemical and Biophysical Research Communications, 197, 869–873.

    Article  PubMed  CAS  Google Scholar 

  11. Pace-Asciak, C. R. (1984). Arachidonic acid epoxides. Demonstration through oxygen-18 labeled oxygen gas studies of an intramolecular transfer of the terminal hydroxyl group of 12S-hydroperoxy-eicosa-5,8,10,14-tetraenoic acid to form hydroxy epoxides. Journal of Biological Chemistry, 259, 8332–8337.

    PubMed  CAS  Google Scholar 

  12. Pace-Asciak, C. R., Klein, J., & Spielberg, S. P. (1986). Epoxide hydratase assay in human platelets using hepoxilin A3 as a lipid substrate. Biochimica et Biophysica Acta, 875, 406–409.

    PubMed  CAS  Google Scholar 

  13. Corey, E. J., & Su, W.-G. (1990). (8R)- and (8S)-Hepoxilin A3. Assignment of configuration and conversion to biologically active conjugates with glutathione. Tetrahedron Letters, 31, 2113–2116.

    Article  CAS  Google Scholar 

  14. Reynaud, D., Demin, P., & Pace-Asciak, C. R. (1994). Hepoxilin A3 formation in the rat pineal gland selectively utilises 12(S)-HPETE but not 12(R)-HPETE. Journal of Biolohical Chemistry, 269, 23976–23980.

    CAS  Google Scholar 

  15. Pace-Asciak, C. R., Reynaud, D., & Demin, P. (1995). Mechanistic aspects of hepoxilin biosynthesis. Journal of Lipid Mediators and Cell Signalling, 12, 307–311.

    Article  PubMed  CAS  Google Scholar 

  16. Pace-Asciak, C. R., Mizuno, K., & Yamamoto, S. (1982). The enzymatic conversion of arachidonic acid into 8,11,12-trihydroxyeicosatrienoic acid. Biochimica et Biophysica Acta, 712, 142–145.

    PubMed  CAS  Google Scholar 

  17. Pace-Asciak, C. R., Martin, J. M., & Corey, E. J. (1986). Hepoxilins, potential endogenous mediators of insulin release. Progress in Lipid Research, 25, 625–628.

    Article  PubMed  CAS  Google Scholar 

  18. Shankaranarayanan, P., Ciccoli, R., & Nigam, S. (2003). Biosynthesis of hepoxilins: evidence for the presence of a hepoxilin synthase activity in rat insulinoma cells. FEBS Letters, 538, 107–112.

    Article  PubMed  CAS  Google Scholar 

  19. Brash, A. R., Yu, Z., Boeglin, W. E., & Schneider, C. (2007). The hepoxilin connection in the epidermis. FEBS Journal, 274, 3494–3502.

    Article  PubMed  CAS  Google Scholar 

  20. Boeglin, W. E., Kim, R. B., & Brash, A. R. (1998). A 12R-lipoxygenase in human skin: mechanistic evidence, hepoxilins in the epidermis. FEBS Journal, 274, 3494–3502.

    Google Scholar 

  21. Jobard, F., Lefevre, C., Karaduman, A., Blanchet-Bardon, C., Emre, S., Weissenbach, J., et al. (2002). Lipoxygenase-3 (ALOXE3) and 12(R)-lipoxygenase (ALOX12B) are mutated in non-bullous congenital ichthyosiform erythroderma (NCIE) linked to chromosome 17p13.1. Human Molecular Genetics, 11, 107–113.

    Article  PubMed  CAS  Google Scholar 

  22. Nigam, S., Zafiriou, M.-P., Deva, R., Kerstin, N., Geilen, C., Ciccoli, R., et al. (2008). Hepoxilin A3 (HXA3) synthase deficiency is causative of a novel ichthyosis form. FEBS Letters, 582, 279–285.

    Article  PubMed  CAS  Google Scholar 

  23. Nigam, S., & Zafiriou, M.-P. (2005). Hepoxilin A3 synthase. Biochemical and Biophysical Research Communications, 336, 161–166.

    Article  Google Scholar 

  24. Pace-Asciak, C. R., Granström, E., & Samuelsson, B. (1983). Arachidonic acid epoxides: isolation and structure of 2 hydroxy epoxide intermediates in the formation of 8,11,12-trihydroxy eicosatrienoic acid and 10,11,12-trihydroxy eicosatrienoic acid. Journal of Biological Chemistry, 258, 6835–6840.

    PubMed  CAS  Google Scholar 

  25. Margalit, A., Sofer, Y., Grossman, S., Reynaud, D., Pace-Asciak, C. R., & Livne, A. (1993). Hepoxilin A3 is the endogenous lipid mediator opposing hypotonic swelling of intact human platelets. Proceeding of the National Academy of Sciences (USA), 90, 2589–2592.

    Article  CAS  Google Scholar 

  26. Samuelsson, B., Dahlen, S. E., Lindgren, A. A., Rouzer, C. A., & Serhan, C. N. (1987). Leukotrienes and lipoxins: structures, biosynthesis and biological effects. Science, 237, 1171–1176.

    Article  PubMed  CAS  Google Scholar 

  27. Carlen, P. L., Gurevich, N., Zhang, L., Wu, P. H., Reynaud, D., & Pace-Asciak, C. R. (1994). Formation and electrophysiological actions of the arachidonic acid metabolites, hepoxilins, at nanomolar concentrations in rat hippocampal slices. Neuroscience, 58, 493–502.

    Article  PubMed  CAS  Google Scholar 

  28. Reynaud, D., Rounova, O., Demin, P. M., Pivnitsky, K. K., & Pace-Asciak, C. R. (1997). Hepoxilin A3 is oxidized by human neutrophils into its omega-hydroxy metabolite by an activity independent of LTB4 omega-hydroxylase. Biochimica et Biophysica Acta Lipids Lipid Metabolism, 1348, 287–298.

    Article  CAS  Google Scholar 

  29. Demin, P. M., Manukina, T. A., Pace-Asciak, C. R., & Pivnitsky, K. K. (1996). Total synthesis of 20-hydroxy hepoxilins, new metabolites of the hepoxilin family. Mendeleev Communications, 4, 130–132.

    Article  Google Scholar 

  30. Reynaud, D., Ali, M., Demin, P., & Pace-Asciak, C. R. (1999). Formation of 14,15-hepoxilins of the A3 and B3 series through a 15-lipoxygenase and hydroperoxide isomerase present in garlic roots. Jounal of Biological Chemistry, 274, 28213–28218.

    Article  CAS  Google Scholar 

  31. Schneider, C., Strayhorn, W. D., Brantley, D. M., Nanney, L. B., Yull, F. E., & Brash, A. R. (2004). Upregulation of 8-lipoxygenase in the dermatitis of IkappaB-alpha-deficient mice. The Journal of Investigative Dermatology, 122, 691–698.

    Article  PubMed  CAS  Google Scholar 

  32. Brunnström, A., Hamberg, M., Griffiths, W. J., Mannervik, B., & Claesson, H. E. (2011). Biosynthesis of 14,15-hepoxilins in human l1236 Hodgkin lymphoma cells and eosinophils. Lipids, 46, 69–79.

    Article  PubMed  Google Scholar 

  33. Nigam, S., Shankarnarayanan, P., Ciccoli, R., Ishdorj, G., Schwarz, K., Petrucev, B., et al. (2004). The rat leukocyte-type 12-lipoxygenase exhibits an intrinsic hepoxilin A3 synthase activity. JBC, 279, 29023–29030.

    Article  CAS  Google Scholar 

  34. Derewlany, L. O., Pace-Asciak, C. R., & Radde, I. C. (1984). Hepoxilin A, hydroxyepoxide metabolite of arachidonic acid stimulates transport of calcium-45 across the guinea-pig visceral yolk sac. Canadian Journal of Physiology and Pharmacology, 62, 1466–1469.

    Article  PubMed  CAS  Google Scholar 

  35. Mills, L., Reynaud, D., & Pace-Asciak, C. R. (1997). Hepoxilin-evoked intracellular reorganization of calcium in human neutrophils: a confocal microscopy study. Experimental Cell Research, 230, 337–341.

    Article  PubMed  CAS  Google Scholar 

  36. Reynaud, D., Demin, P. & Pace-Asciak, C. R. (1995). Coupling of hepoxilin A3-specific binding with calcium-mobilizing actions in human neutrophils. In: K. Schrör and C.R. Pace-Asciak (Eds.), Mediators in the cardiovascular system—regional ischemia. Agents and Actions Supplements, vol 45 (pp. 291–296), Basel: Birkhauser Verlag.

  37. Laneuville, O., Reynaud, D., Grinstein, S., Nigam, S., & Pace-Asciak, C. R. (1993). Hepoxilin A3 inhibits the rise in free intracellular calcium evoked by formyl-methionyl-leucyl-phenylalanine, platelet-activating factor and leukotriene B4. Biochemical Journal, 295, 393–397.

    PubMed  CAS  Google Scholar 

  38. Demin, P. M., Kochev, D. M., Perrier, H., Pace-Asciak, C. R. & Pivnitsky, K. K. (1997). Synthesis of a photoaffinic hepoxilin analog. Medeleev Communications, 1–2.

  39. Bouclier, M., Cavey, D., Kail, N., & Hensby, C. (1990). Experimental models in skin pharmacology. Pharmacological Reviews, 42, 127–154.

    PubMed  CAS  Google Scholar 

  40. Laneuville, O., Corey, E. J., Couture, R., & Pace-Asciak, C. R. (1991). Hepoxilin A3 increases vascular permeability in the rat skin. Eicosanoids, 4, 95–97.

    PubMed  CAS  Google Scholar 

  41. Laneuville, O., Corey, E. J. & Pace-Asciak, C. R. (1991). Hepoxilin A3: a potential mediator of inflammation in the skin with R-stereospecificity. In: M. Bailey (Ed.), Prostaglandins, leukotrienes, lipoxins & PAF. XIth, Washington International Spring Symposium, 1991 (pp. 335–338). New York: Plenum Press. Abstract #155.

  42. Wang, M. M., Demin, P. M., & Pace-Asciak, C. R. (1996). Epimer-specific actions of hepoxilins A3 and B3 on PAF- and bradykinin-evoked vascular permeability in the rat skin in vivo. Advances in Experimental Medicine and Biology, 416, 239–241.

    PubMed  CAS  Google Scholar 

  43. Pace-Asciak, C. R., & Nigam, S. (1991). Hepoxilins modulate second messenger systems in the human neutrophil. In P. Y.-K. Wong & C. Serhan (Eds.), Cell–cell interactions in the release of inflammatory mediators (pp. 133–139). New York: Plenum Press.

    Google Scholar 

  44. Nigam, S., Nodes, S., Cichon, G., Corey, E. J., & Pace-Asciak, C. R. (1990). Receptor-mediated action of hepoxilin A3 releases diacylglycerol and arachidonic acid from human neutrophils. Biochemical and Biophysical Research Communications, 171, 944–948.

    Article  PubMed  CAS  Google Scholar 

  45. Nigam, S. (2007). Hepoxilins—novel enzymatic pathways and clinical significance. FEBS Journal, 274, 3499.

    Google Scholar 

  46. Qiao, N., Lam, J., Reynaud, D., Abdelhaleem, M., & Pace-Asciak, C. R. (2003). The hepoxilin analog PBT-3 induces apoptosis in BCR-ABL-positive K562 leukemia cells. Anticancer Research, 23, 3617–3622.

    PubMed  CAS  Google Scholar 

  47. Pace-Asciak, C. R., & Martin, J. M. (1984). Hepoxilin, a new family of insulin secretagogues formed by intact rat pancreatic islets. Prostagl. Leukotriene and Med., 16, 173–180.

    Article  CAS  Google Scholar 

  48. Pace-Asciak, C. R., Martin, J. M., Corey, E. J., & Su, W.-G. (1985). Endogenous release of hepoxilin A3 from isolated perifused pancreatic islets of Langerhans. Biochemical and Biophysical Research Communications, 128, 942–946.

    Article  PubMed  CAS  Google Scholar 

  49. Pace-Asciak, C. R., Lee, S. P., & Martin, J. M. (1987). In vivo formation of hepoxilin A3 in the rat. Biochemical and Biophysical Research Communications, 147, 881–884.

    Article  PubMed  CAS  Google Scholar 

  50. Pace-Asciak, C. R., Martin, J. M., & Lee, S.-P. (1988). Appearance of prostaglandins, thromboxane B2 and hepoxilin A3 in the circulation of the normal and diabetic (BB) rat after arachidonic acid administration—correlation with plasma insulin. Biochemistry and Cell Biology, 66, 901–909.

    Article  PubMed  CAS  Google Scholar 

  51. Laneuville, O., Couture, R., & Pace-Asciak, C. R. (1992). Hepoxilins sensitize blood vessels to noradrenaline—stereospecificity of action. British Journal of Pharmacology, 105, 297–304.

    PubMed  CAS  Google Scholar 

  52. Laneuville, O., Couture, R., & Pace-Asciak, C. R. (1992). Neurokinin A-induced contraction of guinea-pig isolated trachea: potentiation by hepoxilins. British Journal of Pharmacology, 107, 808–812.

    PubMed  CAS  Google Scholar 

  53. Pace-Asciak, C. R., Reynaud, D., Demin, P., Aslam, R., & Sun, A. (2002). A new family of thromboxane receptor antagonists with secondary thromboxane synthase inhibition. Journal of Pharmacology and Experimental Therapeutics, 301, 618–624.

    Article  PubMed  CAS  Google Scholar 

  54. Margalit, A., Livne, A. A., Funder, J., & Granot, Y. (1993). Initiation of RVD response in human platelets: mechanical-biochemical transduction involves pertussis-toxin-sensitive G protein and phospholipase A2. Journal of Membrane Biology, 136, 1–9.

    Google Scholar 

  55. Margalit, A., & Granot, Y. (1994). Endogenous hepoxilin A3, produced under short duration of high shear-stress, inhibits thrombin-induced aggregation in human platelets. Biochimica et Biophysica Acta Biomembranes, 1190, 173–176.

    Article  CAS  Google Scholar 

  56. Alonso, R., Prieto, L., Hernandez, C., & Mas, M. (1978). Antiandrogenic effects of the pineal gland and metabolism in castrated and intact prepubertal male rats. Journal of Endocrinology, 79, 77–83.

    Article  PubMed  CAS  Google Scholar 

  57. Reynaud, D., Delton, I., Gharib, A., Sarda, N., Lagarde, M., & Pace-Asciak, C. R. (1994). Formation, metabolism, and action of hepoxilin A3 in the rat pineal gland. Journal of Neurochemistry, 62, 126–133.

    Article  PubMed  CAS  Google Scholar 

  58. Belardetti, F., & Siegelbaum, S. A. (1988). Up-and down-modulation of single K + channel function by distinct second messengers. TINS, 11, 232–238.

    PubMed  CAS  Google Scholar 

  59. Piomelli, D. A., Volterra, A., Dale, N., Siegelbaum, S. A., Kandel, E., Schwartz, J. H., et al. (1987). Lipoxygenase metabolites of arachidonic acid as second messengers for presynaptic inhibition of Aplysia sensory neurons. Nature, 328, 38–43.

    Article  PubMed  CAS  Google Scholar 

  60. Pace-Asciak, C. R. (1984). Hemoglobin- and hemin-catalyzed transformation of 12L-hydroperoxy-5, 8, 10, 14-eicosatetraenoic acid. Biochimica et Biophysica Acta, 793, 485–488.

    PubMed  CAS  Google Scholar 

  61. Belardetti, F., Campbell, W. B., Falck, J. R., Demontis, G., & Rosolowsky, M. (1989). Products of heme-catalyzed transformation of the arachidonate derivative 12-HPETE open S-type K+ channels in Aplysia. Neuron, 3, 497–505.

    Article  PubMed  CAS  Google Scholar 

  62. Amer, R. K., Pace-Asciak, C. R., & Mills, L. R. (2003). A lipoxygenase product, hepoxilin A3, enhances nerve growth factor-dependent neurite regeneration post-axotomy in rat superior cervical ganglion neurons in vitro. Neuroscience, 116, 935–946.

    Article  PubMed  CAS  Google Scholar 

  63. Pechan, P. M. (1991). Heat shock proteins and cell proliperation. FEBS Letters (newspaper edition), 280, 1–4.

    Article  CAS  Google Scholar 

  64. Sorger, P. K. (1991). Heat shock factor and the heat shock response. Cell, 65, 363–366.

    Article  PubMed  CAS  Google Scholar 

  65. Chase, M. A., Wheeler, D. S., Lierl, K. M., Hughes, V. S., Wong, H. R., & Page, K. (2007). Hsp72 induces inflammation and regulates cytokine production in airway epithelium through a TLR4- and NF-κB-dependent mechanism. Journal of Immunology, 179, 6318–6324.

    CAS  Google Scholar 

  66. Lin, Z., Laneuville, O., & Pace-Asciak, C. R. (1991). Hepoxilin A3 induces heat shock protein (HSP72) expression in human neutrophils. Biochemical and Biophysical Research Communications, 179, 52–56.

    Article  PubMed  CAS  Google Scholar 

  67. Koller, M., & Konig, W. (1991). 12-hydroxyeicosatetraenoic acid (12-HETE) induces heat shock proteins in human leukocytes. Biochemical and Biophysical Research Communications, 175(3), 804–809.

    Article  PubMed  CAS  Google Scholar 

  68. Yu, Z., Schneider, C., Boeglin, W. E., Marnett, L. J., & Brash, A. R. (2003). The lipoxygenase gene ALOXE3 implicated in skin differentiation encodes a hydroperoxide isomerase. Proceeding of the National Academy of Sciences USA, 100, 9162–9167.

    Article  CAS  Google Scholar 

  69. Qiao, N., Reynaud, D., Demin, P., Halushka, P. V., & Pace-Asciak, C. R. (2003). The thromboxane receptor antagonist PBT-3, a hepoxilin stable analog, selectively antagonizes the TPα isoform in transfected COS-7 cells. Journal of Pharmacology and Experimental Therapeutics, 307, 1142–1147.

    Article  PubMed  CAS  Google Scholar 

  70. Qiao, N., Reynaud, D., Abdelhaleem, M., & Pace-Asciak, C. (2007). Hepoxilin analogs, PBT-3 and PBT-4, cause apoptosis of Gleevec-resistant K562 cells in vitro. In Vivo, 21, 267–271.

    PubMed  CAS  Google Scholar 

  71. Oetzel, C., Jonuleit, T., Gotz, A., Van der Kuip, H., Michels, H., Duyster, J., et al. (2000). The tyrosine kinase inhibitor CGP 57148 (ST1 571) induces apoptosis in BCR-ABL-positive cells by down-regulating BCL-X. Clinical Cancer Research, 6, 1958–1968.

    PubMed  CAS  Google Scholar 

  72. Li, X., Qiao, N., Reynaud, D., Abdelhaleem, M., & Pace-Asciak, C. R. (2005). The hepoxilin analog, PBT-3, inhibits growth of K-562 CML solid tumours in vivo in nude mice. In Vivo, 19, 185–190.

    PubMed  CAS  Google Scholar 

  73. Li, X., Qiao, N., Reynaud, D., Abdelhaleem, M., & Pace-Asciak, C. R. (2005). PBT-3, a hepoxilin stable analog, causes long term inhibition of growth of K562 solid tumours in vivo. Biochemical and Biophysical Research Communications, 338, 158–160.

    Article  PubMed  CAS  Google Scholar 

  74. Sun, Y., & Pang, Z.-L. (2009). Programmed cell death. Postgraduate Medicine, 85, 134–140.

    Article  CAS  Google Scholar 

  75. Modica-Napolitano, J. S., Kulawiec, M., & Singh, K. K. (2007). Mitochondria and human cancer. Current Molecular Medicine, 7, 121–131.

    Article  PubMed  CAS  Google Scholar 

  76. Kawabata, Y., Hirokawa, M., Kitabayashi, A., Takahiro, H., Kuroki, J., & Miura, A. B. (1999). Defective apoptotic signal transduction pathway downstream of caspase-3 in human b-lymphoma cells: a novel mechanism of nuclear apoptosis resistance. Blood, 94, 3523–3530.

    PubMed  CAS  Google Scholar 

  77. Abu-Qare, A. W., & Abou-Donia, M. B. (2001). Biomarkers of apoptosis: release of cytochrome c, activation of caspase-3, induction of 8-hydroxy-2'-deoxyguanosine, increased 3-nitrotyrosine, and alteration of p53 gene. Journal of Toxicology and Environmental Health, Part B: Critical Reviews, 4, 313–332.

    Article  CAS  Google Scholar 

  78. Hurley, B. P., Siccardi, D., Mrsny, R. J., & McCormick, B. A. (2004). Polymorphonuclear cell transmigration induced by Pseudomonas aeruginosa requires the eicosanoid hepoxilin A3. Journal of Immunology, 1, 5712–5720.

    Google Scholar 

  79. McCormick, B. A. (2007). Bacterial-induced hepoxilin A3 secretion as a pro-inflammatory mediator. FEBS Journal, 274, 3513–3518.

    Article  PubMed  CAS  Google Scholar 

  80. Reynaud, D., Sun, A., Demin, P. M., & Pace-Asciak, C. R. (2001). Novel platelet antiaggregating substances. Biochemical and Biophysical Research Communications, 284, 580–582.

    Article  PubMed  CAS  Google Scholar 

  81. Michael Pazos, M., Siccardi, D., Mumy, K. L., Bien, J. D., Louie, S., Shi, H. N., et al. (2008). Multidrug resistance-associated transporter 2 regulates mucosal inflammation by facilitating the synthesis of hepoxilin A3. Journal of Immunology, 181, 8044–8052.

    Google Scholar 

  82. Nakahata, N., Kutsuwa, M., Kyo, R., Kubo, M., Hayashi, K., & Ohizumi, Y. (1998). Analysis of inhibitory effects of scutellariae radix and baicalein on prostaglandin E2 production in rat C6 glioma cells. The American Journal of Chinese Medicine, 26, 311–323.

    Article  PubMed  CAS  Google Scholar 

  83. Zarbock, A., Polanowska-Grabowska, R. K., & Ley, K. (2007). Platelet-neutrophil-interactions: linking hemostasis and inflammation. Blood Reviews, 21, 99–111.

    Article  PubMed  CAS  Google Scholar 

  84. Clark, S. R., Ma, A. C., Tavener, S., McDonald, B., Goodarzi, Z., Kelly, M. M., et al. (2007). Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nature Medicine, 13, 463–469.

    Article  PubMed  CAS  Google Scholar 

  85. McDonald, B., Pittman, K., Menezes, G. B., Hirota, S. A., Slaba, I., Waterhouse, C. C. M., et al. (2010). Intravascular danger signals guide neutrophils to sites of sterile inflammation. Science, 330, 362–366.

    Article  PubMed  CAS  Google Scholar 

  86. Wang, M. M., Reynaud, D., & Pace-Asciak, C. R. (1999). In vivo stimulation of 12(S)-lipoxygenase in the rat skin by bradykinin and platelet activating factor: Formation of 12(S)-HETE and hepoxilins, and actions on vascular permeability. Biochimica et Biophysica Acta Lipids and Lipid Metabolism, 1436, 354–362.

    Article  CAS  Google Scholar 

  87. Antón, R., Puig, L., Esgleyes, T., De Moragas, J. M., & Vila, L. (1998). Occurrence of hepoxilins and trioxilins in psoriatic lesions. The Journal of Investigative Dermatology, 110, 303–310.

    Article  PubMed  Google Scholar 

  88. Marchand, F., Perretti, M., & McMahon, S. B. (2005). Role of the immune system in chronic pain. Nature Reviews Neuroscience, 6, 521–532.

    Article  PubMed  CAS  Google Scholar 

  89. Ferreira, S. H., Lorenzetti, B. B., & Poole, S. (1993). Bradykinin initiates cytokine-mediated inflammatory hyperalgesia. British Journal of Pharmacology, 110, 1227–1231.

    PubMed  CAS  Google Scholar 

  90. Dirig, D. M., Isakson, P. C., & Yaksh, T. L. (1998). Effect of COX-1 and COX-2 inhibition on induction and maintenance of carrageenan-evoked thermal hyperalgesia in rats. Journal of Pharmacology and Experimental Therapeutics, 285, 1031–1038.

    PubMed  CAS  Google Scholar 

  91. Buczynski, M. W., Svensson, C. I., Dumlao, D. S., Fitzsimmons, B. L., Shim, J.-H., Scherbart, T. J., et al. (2010). Inflammatory hyperalgesia induces essential bioactive lipid production in the spinal cord. Journal of Neurochemistry, 114, 961–993.

    Google Scholar 

  92. Gregus, A. M., Dumlao, D. S., Fitzsimmons, B. L., Hua, X.-Y., Dennis, E. A. & Yaksh, T. L. (2010). Spinal 12-lipoxygenases contribute to carrageenan-mediated inflammatory hyperalgesia. IASP. 13th World Congress on Pain, Montreal, 2010, Poster PH 301.

  93. Cooper, J., Zitnik, R., & Matthay, R. (1988). Mechanisms of drug-induced pulmonary disease. Annual Review of Medicine, 39, 395–404.

    Article  PubMed  Google Scholar 

  94. Gurujeyalakshmi, G., & Giri, S. (1995). Molecular mechanisms of anti-fibrotic effect of interferon-gamma in Bleomycin-mouse model of lung fibrosis: downregulation of TGF-beta and procollagen I and III gene expression. Experimental Lung Research, 21, 791–808.

    Article  PubMed  CAS  Google Scholar 

  95. Giri, S., & Hollinger, M. (1996). Effect of nordihydroguaiaretic acid and ibuprofen on bleomycin and hyperoxia-induced changes in lung superoxide dismutase, prostaglandins and lethality. Archives of Toxicology, 70, 271–276.

    Article  PubMed  CAS  Google Scholar 

  96. Kelley, J., Newman, R., & Evans, J. (1980). Bleomycin-induced pulmonary fibrosis in the rat. The Journal of Laboratory and Clinical Medicine, 96, 954–964.

    PubMed  CAS  Google Scholar 

  97. Jankov, R. P., Luo, X., Demin, P., Aslam, R., Hannam, V., Tanswell, A. K., et al. (2002). Hepoxilin analogs inhibit bleomycin-induced pulmonary fibrosis in the mouse. Journal of Pharmacology and Expiremental Therapeutics, 301, 435–440.

    Article  CAS  Google Scholar 

  98. Reynaud, D., Demin, P., & Pace-Asciak, C. R. (1996). Hepoxilin A3-specific binding in human neutrophils. Biochemical Journal, 313, 537–541.

    PubMed  CAS  Google Scholar 

  99. Reynaud, D., Demin, P. M., & Pace-Asciak, C. R. (1995). Hepoxilin binding in human neutrophils. Biochemical and Biophysical Research Communications, 207, 191–194.

    Article  PubMed  CAS  Google Scholar 

  100. Reynaud, D., Demin, P. M. & Pace-Asciak, C. R. (1996). Hepoxilin-specific binding in rat brain. Presented at the 27th Annual Meeting of the American Society for Neurochemistry, Philadelphia, PA, 2–6 March 1996, Abstract #S44A.

Download references

Acknowledgments

The author wishes to acknowledge the support through research grants from the CIHR and OCRF.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Cecil R. Pace-Asciak.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pace-Asciak, C.R. Hepoxilins in cancer and inflammation—use of hepoxilin antagonists. Cancer Metastasis Rev 30, 493–506 (2011). https://doi.org/10.1007/s10555-011-9307-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10555-011-9307-y

Keywords

Navigation