Prostacyclin and Lung Cancer Chemoprevention

  • Robert L. Keith
  • York E. Miller
  • Paul A. BunnJr.
  • Patrick Nana-Sinkam
  • Raphael A. Nemenoff
  • Mark W. Geraci
Part of the Cancer Drug Discovery and Development book series (CDD&D)


Eicosanoids are a family of bioactive lipid metabolites of arachidonic acid (AA). AA is hydrolyzed from membrane phospholipids through the action of phospholipase A2 (PLA2). Free AA can then be metabolized through three major pathways: cyclooxygenase (COX) to produce prostaglandins (PG) and thromboxane, lipoxygenase (LOX) to produce leukotrienes and hydroxy eicosatetraenoic acid (HETES), and cytochrome P-450 to produce epoxyeicosatrienoic acids (EETs). Most studies that have examined eicosanoids and cancer have focused on COX-2 in colon cancer. Elevated COX-2 expression was first demonstrated in colon cancer, in which colon tumors increased COX-2 expression compared to normal colon tissues (1).


Lung Cancer Adenomatous Polyposis Coli Primary Pulmonary Hypertension Tumor Multiplicity Lung Tumorigenesis 
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  1. 1.
    Kargman SL, O’Neill GP, Vickers PJ, et al. Expression of prostaglandin G/H synthase-1 and -2 protein in human colon cancer. Cancer Res 1995;55:2556–2559.PubMedGoogle Scholar
  2. 2.
    Kutchera W, Jones DA, Matsunami N, et al. Prostaglandin H synthase 2 is expressed abnormally in human colon cancer: evidence for a transcriptional effect. Proc Natl Acad Sci USA 1996;93:4816–4820.PubMedCrossRefGoogle Scholar
  3. 3.
    Rao CV, Rivenson A, Simi B, et al. Chemoprevention of colon carcinogenesis by sulindac, a nonsteroidal anti-inflammatory agent. Cancer Res 1995;55:1464–1472.PubMedGoogle Scholar
  4. 4.
    Sheng H, Shao J, Kirkland SC, et al. Inhibition of human colon cancer cell growth by selective inhibition of cyclooxygenase-2. J Clin Investig 1997;99:2254–2259.PubMedCrossRefGoogle Scholar
  5. 5.
    Sheng GG, Shao J, Sheng H, et al. A selective cyclooxygenase 2 inhibitor suppresses the growth of H-ras-transformed rat intestinal epithelial cells. Gastroenterology 1997;113:1883–1891.PubMedCrossRefGoogle Scholar
  6. 6.
    Thun MJ. Aspirin, NSAIDs, and digestive tract cancers. Cancer Metastasis Rev 1994;13:269–277.PubMedCrossRefGoogle Scholar
  7. 7.
    Oshima M, Dinchuk JE, Kargman SL, et al. Suppression of intestinal polyposis in Apc delta716 knockout mice by inhibition of cyclooxygenase 2 (COX-2). Cell 1996;87:803–809.PubMedCrossRefGoogle Scholar
  8. 8.
    Liu CH, Chang SH, Narko K, et al. Overexpression of cyclooxygenase-2 is sufficient to induce tumorigenesis in transgenic mice. J Biol Chem 2001;276:18,563–18,569.Google Scholar
  9. 9.
    Schreinemachers DM, Everson RB. Aspirin use and lung, colon, and breast cancer incidence in a prospective study. Epidemiology 1994;5:138–146.PubMedCrossRefGoogle Scholar
  10. 10.
    Hubbard MJ, Cohen P. On target with a new mechanism for the regulation of protein phosphorylation. Trends Biochem Sci 1993;18:172–177.PubMedCrossRefGoogle Scholar
  11. 11.
    Lau SS, McMahon JB, McMenamin MG, et al. Metabolism of arachidonic acid in human lung cancer cell lines. Cancer Res 1987;47:3757–3762.PubMedGoogle Scholar
  12. 12.
    Hubbard WC, Alley MC, McLemore TL, Boyd MR. Evidence for thromboxane biosynthesis in established cell lines derived from human lung adenocarcinomas. Cancer Res 1988;48:2674–2677.PubMedGoogle Scholar
  13. 13.
    Avis IM, Jett M, Boyle T, et al. Growth control of lung cancer by interruption of 5-lipoxygenase-mediated growth factor signaling. J Clin Investig 1996;97:806–813.PubMedCrossRefGoogle Scholar
  14. 14.
    Huang M, Stolina M, Sharma S, et al. Non-small cell lung cancer cyclooxygenase-2-dependent regulation of cytokine balance in lymphocytes and macrophages: up-regulation of interleukin 10 and down-regulation of interleukin 12 production. Cancer Res 1998;58:1208–1216.PubMedGoogle Scholar
  15. 15.
    Hida T, Yatabe Y, Achiwa H, et al. Increased expression of cyclooxygenase 2 occurs frequently in human lung cancers, specifically in adenocarcinomas. Cancer Res 1998;58:3761–3764.PubMedGoogle Scholar
  16. 16.
    Wolff H, Saukkonen K, Anttila S, et al. Expression of cyclooxygenase-2 in human lung carcinoma. Cancer Res 1998;58:4997–5001.PubMedGoogle Scholar
  17. 17.
    Heasley LE, Thaler S, Nicks M, et al. Induction of cytosolic phospholipase A2 by oncogenic Ras in human non-small cell lung cancer. J Biol Chem 1997;272:14,501–14,504.CrossRefGoogle Scholar
  18. 18.
    Bauer AK, Dwyer-Nield LD, Malkinson AM. High cyclooxygenase 1 (COX-1) and cyclooxygenase 2 (COX-2) contents in mouse lung tumors. Carcinogenesis 2000;21:543–550.PubMedCrossRefGoogle Scholar
  19. 19.
    Hida T, Leyton J, Makheja AN, et al. Non-small cell lung cancer cycloxygenase activity and proliferation are inhibited by non-steroidal antiinflammatory drugs. Anticancer Res 1998;18:775–782.PubMedGoogle Scholar
  20. 20.
    Duperron C, Castonguay A. Chemopreventive efficacies of aspirin and sulindac against lung tumorigenesis in A/J mice. Carcinogenesis 1997;18:1001–1006.PubMedCrossRefGoogle Scholar
  21. 21.
    Takaku K, Sonoshita M, Sasaki N, et al. Suppression of intestinal polyposis in Apc(delta 716) knockout mice by an additional mutation in the cytosolic phospholipase A(2) gene. J Biol Chem 2000;275:34,013–34,016.Google Scholar
  22. 22.
    Hong KH, Bonventre JC, O’Leary E, et al. Deletion of cytosolic phospholipase A(2) suppresses Apc(Min)-induced tumorigenesis. Proc Natl Acad Sci USA 2001;98:3935–3939.PubMedCrossRefGoogle Scholar
  23. 23.
    MacPhee M, Chepenik KP, Liddell RA, et al. The secretory phospholipase A2 gene is a candidate for the Mom 1 locus, a major modifier of ApcMin-induced intestinal neoplasia. Cell 1995;81:957–966.PubMedCrossRefGoogle Scholar
  24. 24.
    Yoshimatsu K, Altorki NK, Golijanin D, et al. Inducible prostaglandin E synthase is overexpressed in non-small cell lung cancer. Clin Cancer Res 2001;7:2669–2674.PubMedGoogle Scholar
  25. 25.
    Tsujii M, DuBois RN. Alterations in cellular adhesion and apoptosis in epithelial cells overexpressing prostaglandin endoperoxide synthase 2. Cell 1995;83:493–501.PubMedCrossRefGoogle Scholar
  26. 26.
    Tsujii M, Kawano S, DuBois RN. Cyclooxygenase-2 expression in human colon cancer cells increases metastatic potential. Proc Natl Acad Sci USA 1997;94:3336–3340.PubMedCrossRefGoogle Scholar
  27. 27.
    Casibang M, Purdom S, Jakowlew S, et al. Prostaglandin E2 and vasoactive intestinal peptide increase vascular endothe-lial cell growth factor mRNAs in lung cancer cells. Lung Cancer 2001;31:203–212.PubMedCrossRefGoogle Scholar
  28. 28.
    Marnett LJ, Siedlik PH, Ochs RC, et al. Mechanism of the stimulation of prostaglandin H synthase and prostacyclin synthase by the antithrombotic and antimetastatic agent, nafazatrom. Mol Pharmacol 1984;26:328–335.PubMedGoogle Scholar
  29. 29.
    Kujubu DA, Herschman HR. Dexamethasone inhibits mitogen induction of the TIS 10 prostaglandin synthase/cyclooxygenase gene. J Biol Chem 1992;267:7991–7994.PubMedGoogle Scholar
  30. 30.
    Kujubu DA, Fletcher BS, Varnum BC. TIS 10, a phorbol ester tumor promoter-inducible mRNA from Swiss 3T3 cells, encodes a novel prostaglandin synthase/cyclooxygenase homologue. J Biol Chem 1991;266:12,866–12,872.Google Scholar
  31. 31.
    Hara S, Miyata A, Yokoyama C, et al. Isolation and molecular cloning of prostacyclin synthase from bovine endothelial cells. J Biol Chem 1994;269:19,897–19,903.Google Scholar
  32. 32.
    Shaul PW, Kinane B, Farrar MA, et al. Prostacyclin production and mediation of adenylate cyclase activity in the pulmonary artery. Alterations after prolonged hypoxia in the rat. J Clin Investig 1991;88:447–455.PubMedCrossRefGoogle Scholar
  33. 33.
    Halushka PV, Mais DE, Morinelli TA. Thromboxane and prostacyclin receptors. Prog Clin BiolRes1989;301:21–28.Google Scholar
  34. 34.
    Bunting S, Gryglewski R, Moncada S, Vane JR. Arterial walls generate from prostaglandin endoperoxides a substance (prostaglandin X) which relaxes strips of mesenteric and coeliac arteries and inhibits platelet aggregation. Prostaglandins 1976;12:897–913.PubMedGoogle Scholar
  35. 35.
    Moncada S, Vane JR. Pharmacology and endogenous roles of prostaglandin endoperoxides, thromboxane A2, and prostacyclin. Pharmacol Rev 1978;30:293–331.PubMedGoogle Scholar
  36. 36.
    Libby P, Warner SJ, Friedman GB. Interleukin I: a mitogen for human vascular smooth muscle cells that induces the release of growth-inhibitory prostanoids. J Clin Investig 1988;81:487–498.PubMedCrossRefGoogle Scholar
  37. 37.
    Jugdutt BI, Hutchins GM, Bulkley BH, Becker LC. Myocardial infarction in the conscious dog: three-dimensional mapping of infarct, collateral flow and region at risk. Circulation 1979;60:1141–1150.PubMedCrossRefGoogle Scholar
  38. 38.
    Ribeiro LG, Brandon TA, Hopkins DG, et al. Prostacyclin in experimental myocardial ischemia: effects on hemodynamics, regional myocardial blood flow, infarct size and mortality. Am J Cardiol 1981;47:835–840.PubMedCrossRefGoogle Scholar
  39. 39.
    Jemal A, Thomas A, Murray T, Thun M. Cancer statistics, 2002. CA Cancer J Clin 2002;52:23–47.PubMedCrossRefGoogle Scholar
  40. 40.
    Malkinson AM. Molecular comparison of human and mouse pulmonary adenocarcinomas. Exp Lung Res 1998;24:541–555.PubMedCrossRefGoogle Scholar
  41. 41.
    Rioux N, Castonguay A. Prevention of NNK-induced lung tumorigenesis in A/J mice by acetylsalicylic acid and NS-398. Cancer Res 1998;58:5354–5360.PubMedGoogle Scholar
  42. 42.
    Moody TW, Leyton J, Martinez A, et al. Lipoxygenase inhibitors prevent lung carcinogenesis and inhibit non-small cell lung cancer growth. Exp Lung Res 1998;24:617–628.PubMedCrossRefGoogle Scholar
  43. 43.
    Vane JR. Prostacyclin: a hormone with a therapeutic potential. The Sir Henry Dale Lecture for 1981. J Endocrinol 1982;95:3P-43P.PubMedGoogle Scholar
  44. 44.
    Dusting GJ, Moncada S, Vane JR. Prostacyclin: its biosynthesis, actions, and clinical potential. Adv Prostaglandin Thromboxane Leukot Res 1982;10:59–106.PubMedGoogle Scholar
  45. 45.
    Honn KV, Cicone B, Skoff A. Prostacyclin: a potent antimetastatic agent. Science 1981;212:1270–1272.PubMedCrossRefGoogle Scholar
  46. 46.
    Schirner M, Schneider MR. Inhibition of metastasis by cicaprost in rats with established SMT2A mammary carcinoma growth. Cancer Detect Prey 1997;21:44–50.Google Scholar
  47. 47.
    Hubbard WC, Alley MC, Gray GN, et al. Evidence for prostanoid biosynthesis as a biochemical feature of certain subclasses of non-small cell carcinomas of the lung as determined in established cell lines derived from human lung tumors. Cancer Res 1989;49:826–832.PubMedGoogle Scholar
  48. 48.
    Tuder RM, Cool CD, Geraci MW, et al. Prostacyclin synthase expression is decreased in lungs from patients with severe pulmonary hypertension. Am J Respir Crit Care Med 1999;159:1925–1932.PubMedGoogle Scholar
  49. 49.
    Keith RL, Miller YE, Hoshikawa Y, et al. Manipulation of pulmonary prostacyclin synthase expression prevents murine lung cancer. Cancer Res 2002;62:734–740.PubMedGoogle Scholar
  50. 50.
    Namba T, Oida H, Sugimoto Y, et al. cDNA cloning of a mouse prostacyclin receptor. Multiple signaling pathways and expression in thymic medulla. Biol Chem 1994;269:9986–9992.Google Scholar
  51. 51.
    Boie Y, Rushmore TH, Darmon-Goodwin A, et al. Cloning and expression of a cDNA for the human prostanoid IP receptor. J Biol Chem 1994;269:12,173–12,178.Google Scholar
  52. 52.
    Kobayashi T, Kiriyama M, Hirata T, et al. Identification of domains conferring ligand binding specificity to the prostanoid receptor. Studies on chimeric prostacyclin/prostaglandin D receptors. J Biol Chem 1997;272:15,154–15,160.Google Scholar
  53. 53.
    Smyth EM, Li WH, FitzGerald GA. Phosphorylation of the prostacyclin receptor during homologous desensitization. A critical role for protein kinase C. J Biol Chem 1998;273:23,258–23,266.CrossRefGoogle Scholar
  54. 54.
    Hayes JS, Lawler OA, Walsh MT, Kinsella BT. The prostacyclin receptor is isoprenylated. Isoprenylation is required for efficient receptor-effector coupling. J Biol Chem 1999;274:23,707–23,718.Google Scholar
  55. 55.
    Murata T, Ushikubi F, Matsuoka T, et al. Altered pain percep-tion and inflammatory response in mice lacking prostacyclin receptor. Nature 1997;388:678–682.PubMedCrossRefGoogle Scholar
  56. 56.
    Hoshikawa Y, Voelkel NF, Gesell TL, et al. Prostacyclin receptor-dependent modulation of pulmonary vascular remodeling. Am J Respir Crit Care Med 2001;164:314–318.PubMedGoogle Scholar
  57. 57.
    Lim H, Gupta RA, Ma WG, et al. Cyclo-oxygenase-2-derived prostacyclin mediates embryo implantation in the mouse via PPAR delta. Genes Dev 1999;13:1561–1574.PubMedCrossRefGoogle Scholar
  58. 58.
    Schmidt A, Endo N, Rutledge SJ, et al. Identification of a new member of the steroid hormone receptor superfamily that is activated by a peroxisome proliferator and fatty acids. Mol Endocrinol 1992;6:1634–1641.PubMedCrossRefGoogle Scholar
  59. 59.
    Mangelsdorf DJ, Thummel C, Beato M, et al. The nuclear receptor superfamily: the second decade. Cell 1995;83:835–839.PubMedCrossRefGoogle Scholar
  60. 60.
    Willson TM, Brown PJ, Sternbach DD, Henke BR. The PPARs: from orphan receptors to drug discovery. J Med Chem 2000;43:527–550.PubMedCrossRefGoogle Scholar
  61. 61.
    Lim H, Paria BC, Das SK, et al. Multiple female reproductive failures in cyclooxygenase 2-deficient mice. Cell 1997;91:197–208.PubMedCrossRefGoogle Scholar
  62. 62.
    Gupta RA, Tan J, Krause WF, et al. Prostacyclin-mediated activation of peroxisome proliferator-activated receptor delta in colorectal cancer. Proc Natl Acad Sci USA 2000;97:13,275–13,280.CrossRefGoogle Scholar
  63. 63.
    He TC, Chan TA, Vogelstein B, Kinzler KW. PPARδ is an APC-regulated target of nonsteroidal anti-inflammatory drugs. Cell 1999;99:335–345.PubMedCrossRefGoogle Scholar
  64. 64.
    Forman BM, Chen J, Evans RM. Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors a and δ. Proc Natl Acad Sci USA 1997;94:4312–4317.CrossRefGoogle Scholar
  65. 65.
    Vanden Heuvel JP. Peroxisome proliferator-activated receptors: a critical link among fatty acids, gene expression and carcinogenesis. J Nutr 1999;129:575–580.Google Scholar
  66. 66.
    Oreffo VI, Robinson S, You M. Decreased expression of the adenomatous polyposis coli (Apc) and mutated in colorectal cancer (Mcc) genes in mouse lung neoplasia. Mol Carcinog 1998;21:37–49.PubMedCrossRefGoogle Scholar
  67. 67.
    DuBois RN, Abramson SB, Crofford L, et al. Cyclooxygenase in biology and disease FASEB J 1998;12:1063–1073.PubMedGoogle Scholar
  68. 68.
    Tsujii M, Kawano S, Tsuji S, et al. Cyclooxygenase regulates angiogenesis induced by colon cancer cells. Cell 1998;93:705–716.PubMedCrossRefGoogle Scholar
  69. 69.
    Geraci MW, Gao B, Shepherd DC, et al. Pulmonary prostacyclin synthase overexpression in transgenic mice protects against development of hypoxic pulmonary hypertension. J Clin Investig 1999;103:1509–1515.PubMedCrossRefGoogle Scholar
  70. 70.
    Korfhagen TR, Glasser SW, Wert SE, et al. Cis-acting sequences from a human surfactant protein gene confer pulmonary-specific gene expression in transgenic mice. Proc Natl Acad Sci USA 1990;87:6122–6126.PubMedCrossRefGoogle Scholar
  71. 71.
    Mirvish SS. The carcinogenic action and metabolism of urethan and N-hydroxyurethan. Adv Cancer Res 1968:11:1–42.PubMedCrossRefGoogle Scholar
  72. 72.
    Malkinson AM, Koski KM, Evans WA, Festing MF. Butylated hydroxytoluene exposure is necessary to induce lung tumors in BALB mice treated with 3-methylcholanthrene. Cancer Res 1997;57:2832–2834.PubMedGoogle Scholar
  73. 73.
    Witschi H, Malkinson AM, Thompson JA. Metabolism and pulmonary toxicity of butylated hydroxytolulene, in Metabolic Activation and Toxicity of Chemical Agents to Lung Tissues and Cells. 1st ed. Gram TE, ed. Pergamon Press, New York, 1993, pp.185–212.Google Scholar
  74. 74.
    Barst RJ, Rubin LJ, Long WA, et al. A comparison of contin-uous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. The Primary Pulmonary Hypertension Study Group. N Engl J Med 1996;334:296–302.PubMedCrossRefGoogle Scholar
  75. 75.
    Black CM, Halkier-Sorensen L, Belch JJ, et al. Oral iloprost in Raynaud’s phenomenon secondary to systemic sclerosis: a multicentre, placebo-controlled, dose-comparison study. Br J Rheumatol 1998;37:952–960.PubMedCrossRefGoogle Scholar
  76. 76.
    Hildebrand M. Pharmacokinetics and tolerability of oral iloprost in thromboangiitis obliterans patients. Eur J Clin Pharmacol 1997;53:51–56.PubMedCrossRefGoogle Scholar
  77. 77.
    Sasaki H, Tanahashi M, Yukiue H, et al. Decreased perioxisome proliferator-activated receptor gamma gene expression was correlated with poor prognosis in patients with lung cancer. Lung Cancer 2002;36:71–76.PubMedCrossRefGoogle Scholar
  78. 78.
    Jaeckel EC, Raja S, Tan J, et al. Correlation of expression of cyclooxygenase-2, vascular endothelial growth factor, and peroxisome proliferator-activated receptor δ with head and neck squamous cell carcinoma. Arch Otolaryngol Head Neck Surg 2001;127:1253–1259.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2004

Authors and Affiliations

  • Robert L. Keith
  • York E. Miller
  • Paul A. BunnJr.
  • Patrick Nana-Sinkam
  • Raphael A. Nemenoff
  • Mark W. Geraci

There are no affiliations available

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