Mode of Action of Aspirin as a Chemopreventive Agent

  • Melania Dovizio
  • Annalisa Bruno
  • Stefania Tacconelli
  • Paola Patrignani
Part of the Recent Results in Cancer Research book series (RECENTCANCER, volume 191)

Abstract

Aspirin taken for several years at doses of at least 75 mg daily reduced long-term incidence and mortality due to colorectal cancer. The finding of aspirin benefit at low-doses given once daily, used for cardioprevention, locates the antiplatelet effect of aspirin at the center of its antitumor efficacy. In fact, at low-doses, aspirin acts mainly by an irreversible inactivation of platelet cyclooxygenase (COX)-1 in the presystemic circulation, which translates into a long-lasting inhibition of platelet function. Given the short half-life of aspirin in the human circulation(approximately 20 min) and the capacity of nucleated cells to resynthesize the acetylated COX-isozyme(s), it seems unlikely that a nucleated cell could be the target of aspirin chemoprevention. These findings convincingly suggest that colorectal cancer and atherothrombosis may share a common mechanism of disease, i.e. platelet activation in response to epithelial(in tumorigenesis) and endothelial(in tumorigenesis and atherothrombosis) injury. Activated platelets may also enhance the metastatic potential of cancer cells (through a direct interaction and/or the release of soluble mediators or exosomes) at least in part by inducing the overexpression of COX-2. COX-independent mechanisms of aspirin, such as the inhibition of NF-kB signaling and Wnt/β-catenin signaling and the acetylation of extra-COX proteins, have been suggested to play a role in its chemopreventive effects. However, their relevance remains to be demonstrated in vivo at clinical doses.

Keywords

Familial Adenomatous Polyposis Chemopreventive Effect Irreversible Inactivation Serum TXB2 Washed Human Platelet 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Abbreviations

15R-HETE

15R-hydroxyeicosapentaenoic acid

5-LOX

5-lipoxygenase

ADP

Adenosine diphosphate

apaf-1

Apoptotic protease activating factor-1

AA

Arachidonic acid

CRC

Colorectal cancer

COX

Cyclooxygenase

EGFR

Epidermal growth factor receptor

ERK

Extracellular signal-regulated kinase

FAP

Familial adenomatous polyposis

FGF

Fibroblast growth factor

IGF

Insulin-like growth factor

IL

Interleukin

LPS

Bacterial endotoxin

MPs

Microparticles

mPGES-1

Microsomal PGE2 synthase-1

NK

Natural killer

NSAID

Nonsteroidal anti-inflammatory drug

NF-kB

Nuclear factor kappa B

PDGF

Platelet-derived growth factor

PDGF

Platelet-derived growth factor

PGI2

Prostacyclin

PG

Prostaglandin

PKC

Protein kinase C

Ser

Serine

S1P

Sphingosine-1-phosphate

Lef

T-cell factor (Tcf)/lymphoid enhancer factor

TX

Thromboxane

TIMP

Tissue inhibitor of metalloproteinases

TCIPA

Tumor cell-induced platelet aggregation

TXAS

TXA2 synthase

VEGF

Vascular endothelial growth factor

Notes

Acknowledgements

This work was supported by research funding from the Associazione Italiana per la Ricerca sul Cancro (AIRC) to Paola Patrignani. We would like to thank, for fruitful discussions and suggestions, Dr Carlo Patrono (Catholic University, Rome, Italy), Luis A Garcia Rodriguez (CEIFE, Madrid, Spain) and Angel Lanas (University of Zaragoza, Spain). We apologize to our colleagues for not being able to reference all primary work due to space limitations.

References

  1. Alfonso LF, Srivenugopal KS, Arumugam TV et al (2009a) Aspirin inhibits camptothecin-induced p21CI P1 levels and potentiates apoptosis in human breast cancer cells. Int J Oncol 34:597–608PubMedGoogle Scholar
  2. Alfonso LF, Srivenugopal KS, Bhat GJ (2009b) Does aspirin acetylate multiple cellular proteins? Mol Med Report 2:533–537PubMedGoogle Scholar
  3. Archer SY, Hodint RA (1999) Histone acetylation and cancer. Curr Opin Genet Dev 9:171–174PubMedGoogle Scholar
  4. Baigent C and Antithrombotic Trialists’ Collaboration (2002) Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high-risk patients. BMJ 324:71–86Google Scholar
  5. Baron JA, Cole BF, Sandler RS et al (2003) A randomized trial of aspirin to prevent colorectal adenomas. N Engl J Med 348:891–899PubMedGoogle Scholar
  6. Bastida E, Escolar G, Ordinas A et al (1986) Morphometric evaluation of thrombogenesis by microvesicles from human tumor cell lines with thrombin-dependent (U87MG) and adenosine diphosphate-dependent (SKNMC) platelet-activating mechanisms. J Lab Clin Med 108:622–627PubMedGoogle Scholar
  7. Benamouzig R, Deyra J, Martin A et al (2003) Daily soluble aspirin and prevention of colorectal adenoma recurrence: one-year results of the APACC trial. Gastroenterology 125:328–336PubMedGoogle Scholar
  8. Bertagnolli MM, Eagle CJ, Zauber AG et al (2006) Celecoxib for the prevention of sporadic colorectal adenomas. N Engl J Med 355:873–884PubMedGoogle Scholar
  9. Bos CL, Kodach LL, van den Brink GR et al (2006) Effect of aspirin on the Wnt/beta-catenin pathway is mediated via protein phosphatase 2A. Oncogene 25:6447–6456PubMedGoogle Scholar
  10. Bours V, Bentires-Alj M, Hellin AC et al (2000) Nuclear factor-kappa B, cancer, and apoptosis. Biochem Pharmacol 60:1085–1089PubMedGoogle Scholar
  11. Cao Y, Prescott SM (2002) Many actions of cyclooxygenase-2 in cellular dynamics and in cancer. J Cell Physiol 90:279–286Google Scholar
  12. Capone ML, Tacconelli S, Di Francesco L et al (2007) Pharmacodynamic of cyclooxygenase inhibitors in humans. Prostaglandins Other Lipid Mediat 82:85–94PubMedGoogle Scholar
  13. Capone ML, Tacconelli S, Sciulli MG et al (2004) Clinical pharmacology of platelet, monocyte, and vascular cyclooxygenase inhibition by naproxen and low-dose aspirin in healthy subjects. Circulation 109:1468–1471PubMedGoogle Scholar
  14. Cervi D, Yip TT, Bhattacharya N et al (2008) Platelet-associated PF-4 as a biomarker of early tumor growth. Blood 111:1201–1207PubMedGoogle Scholar
  15. Cha YI, DuBois RN (2007) NSAIDs and cancer prevention: targets downstream of COX-2. Annu Rev Med 58:239–252PubMedGoogle Scholar
  16. Charman WN, Charman SA, Monkhouse DC et al (1993) Biopharmaceutical characterisation of a low-dose (75 mg) controlled-release aspirin formulation. Br J Clin Pharmac 36:470–473Google Scholar
  17. Chen Z, Hagler J, Palombella VJ et al (1995) Signal-induced site-specific phosphorylation targets I kappa B alpha to the ubiquitin-proteasome pathway. Genes Dev 9:1586–1597PubMedGoogle Scholar
  18. Chulada PC, Thompson MB, Mahler JF et al (2000) Genetic disruption of Ptgs-1, as well as Ptgs-2, reduces intestinal tumorigenesis in Min mice. Cancer Res 60:4705–4708PubMedGoogle Scholar
  19. Cipollone F, Patrignani P, Greco A et al (1997) Differential suppression of thromboxane biosynthesis by indobufen and aspirin in patients with unstable angina. Circulation 96:1109–1116PubMedGoogle Scholar
  20. Clarke RJ, Mayo G, Price P et al (1991) Suppression of thromboxane A2 but not of systemic prostacyclin by controlled-release aspirin. N Engl J Med 325:1137–1141PubMedGoogle Scholar
  21. Collier JC, Flower RJ (1971) Effect of Aspirin on human seminal prostaglandins. Lancet ii:852–853Google Scholar
  22. Creagh EM, Conroy H, Martin SJ (2003) Caspase-activation pathways in apoptosis and immunity. Immunol Rev 193:10–21PubMedGoogle Scholar
  23. Cuzick J, Otto F, Baron JA et al (2009) Aspirin and non-steroidal anti-inflammatory drugs for cancer prevention: an international consensus statement. Lancet Oncol 10:501–507PubMedGoogle Scholar
  24. Davì G, Patrono C (2007) Platelet activation and atherothrombosis. N Engl J Med 357:2482–2494PubMedGoogle Scholar
  25. Delattre O, Olschwang S, Law DJ et al (1989) Multiple genetic alterations in distal and proximal colorectal cancer. Lancet 2:353–356PubMedGoogle Scholar
  26. Di Francesco L, Totani L, Dovizio M et al (2009) Induction of prostacyclin by steady laminar shear stress suppresses tumor necrosis factor-alpha biosynthesis via heme oxygenase-1 in human endothelial cells. Circ Res 104:506–513PubMedGoogle Scholar
  27. Dixon DA, Tolley ND, Bemis-Standoli K et al (2006) Expression of COX-2 in platelet-monocyte interactions occurs via combinatorial regulation involving adhesion and cytokine signaling. J Clin Invest 116:2727–2738PubMedGoogle Scholar
  28. Dixon DA, Tolley ND, King PH et al (2001) Altered expression of the mRNA stability factor HuR promotes cyclooxygenase-2 expression in colon cancer cells. J Clin Invest 2108:1657–1665Google Scholar
  29. Donnini S, Finetti F, Solito R et al (2007) EP2 prostanoid receptor promotes squamous cell carcinoma growth through epidermal growth factor receptor transactivation and iNOS and ERK1/2 pathways. FASEB J 21:2418–2430PubMedGoogle Scholar
  30. Dovizio M, Tacconelli S, Ricciotti E et al (2012) Effects of celecoxib on prostanoid biosynthesis and circulating angiogenesis proteins in familial adenomatous polyposis. J Pharmacol Exp Ther 341:242–250PubMedGoogle Scholar
  31. Dreser H (1899) Pharmakologisches über aspirin (acetylsalicylsäure). Pfluger’s Arch 76:306–318Google Scholar
  32. Evangelista V, Manarini S, Di Santo A et al (2006) De novo synthesis of cyclooxygenase-1 counteracts the suppression of platelet thromboxane biosynthesis by aspirin. Circ Res 98:593–595PubMedGoogle Scholar
  33. Ferreira SH, Moncada S, Vane JR (1971) Indomethacin and Aspirin abolish prostaglandin release from spleen. Nature 231:237–239Google Scholar
  34. Fierro IM, Kutok JL, Serhan CN (2002) Novel lipid mediator regulators of endothelial cell proliferation and migration: aspirin-triggered-15R-lipoxin A(4) and lipoxin A(4). J Pharmacol Exp Ther 300:385–392PubMedGoogle Scholar
  35. FitzGerald GA (2003) COX-2 and beyond: Approaches to prostaglandin inhibition in human disease. Nat Rev Drug Discov 2:879–890PubMedGoogle Scholar
  36. García Rodríguez LA, Hernández-Díaz S, de Abajo FJ (2001) Association between aspirin and upper gastrointestinal complications: systematic review of epidemiologic studies. Br J Clin Pharmacol 52:563–571PubMedGoogle Scholar
  37. García Rodríguez LA, Lin KJ, Hernández-Díaz S et al (2011) Risk of upper gastrointestinal bleeding with low-dose acetylsalicylic acid alone and in combination with clopidogrel and other medications. Circulation 2011(123):1108–1115Google Scholar
  38. Gay LJ, Felding-Habermann B (2011) Contribution of platelets to tumour metastasis. Nat Rev Cancer 11:123–134PubMedGoogle Scholar
  39. Geest CR, Coffer PJ (2009) MAPK signaling pathways in the regulation of hematopoiesis. J Leukoc Biol 86:237–250PubMedGoogle Scholar
  40. Gilroy DW (2005) The role of aspirin-triggered lipoxins in the mechanism of action of aspirin. Prostaglandins Leukot Essent Fatty Acids 73:203–210PubMedGoogle Scholar
  41. Grilli M, Pizzi M, Memo M et al (1996) Neuroprotection by aspirin and sodium salicylate through blockade of NF-kB activation. Science 274:1383–1385PubMedGoogle Scholar
  42. Grosser T, Fries S, FitzGerald GA (2006) Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities. J Clin Invest 116:4–15PubMedGoogle Scholar
  43. Gu Q, Wang JD, Xia HH et al (2005) Activation of the caspase-8/Bid and Bax pathways in aspirin-induced apoptosis in gastric cancer. Carcinogenesis 26:541–546PubMedGoogle Scholar
  44. Hanif R, Pittas A, Feng Y et al (1996) Effects of nonsteroidal anti-inflammatory drugs on proliferation and on induction of apoptosis in colon cancer cells by a prostaglandin-independent pathway. Biochem Pharmacol 52:237–245PubMedGoogle Scholar
  45. Harper KA, Tyson-Capper AJ (2008) Complexity of COX-2 gene regulation. Biochem Soc Trans 36:543–545PubMedGoogle Scholar
  46. Hemler M, Lands WEM, Smith WL (1976) Purification of the cyclooxygenase that forms prostaglandins: demonstration of two forms of iron in the holoenzyme. J Biol Chem 251:5575–5579PubMedGoogle Scholar
  47. Honn K (1983) Inhibition of tumor cell metastasis by modulation of the vascular prostacyclin/thromboxane A2 system. Clin Exp Metastasis 1:103–114PubMedGoogle Scholar
  48. Iacopetta B (2002) Are there two sides to colorectal cancer? Int J Cancer 101:403–408PubMedGoogle Scholar
  49. Italiano JE Jr, Richardson JL, Patel-Hett S et al (2008) Angiogenesis is regulated by a novel mechanism: pro- and antiangiogenic proteins are organized into separate platelet alpha granules and differentially released. Blood 111:1227–1233PubMedGoogle Scholar
  50. Jana NR (2008) NSAIDs and apoptosis. Cell Mol Life Sci 65:1295–1301PubMedGoogle Scholar
  51. Janowska-Wieczorek A, Wysoczynski M, Kijowski J et al (2005) Microvesicles derived from activated platelets induce metastasis and angiogenesis in lung cancer. Int J Cancer 113:752–760PubMedGoogle Scholar
  52. Jurasz P, Alonso-Escolano D, Radomski MW (2004) Platelet–cancer interactions: mechanisms and pharmacology of tumour cell-induced platelet aggregation. Br J Pharmacol 143:819–826PubMedGoogle Scholar
  53. Kang YJ, Mbonye UR, DeLong CJ et al (2007) Regulation of intracellular cyclooxygenase levels by gene transcription and protein degradation. Prog Lipid Res 46:108–125PubMedGoogle Scholar
  54. Kopp E, Ghosh S (1994) Inhibition of NF-kappa B by sodium salicylate and aspirin. Science 265:956–959PubMedGoogle Scholar
  55. Kujubu DA, Fletcher BS, Varnum BC (1991) TIS10, a phorbol ester tumor promoter-inducible mRNA from Swiss 3T3 cells, encodes a novel prostaglandin synthase/cyclooxygenase homologue. J Biol Chem 266:12866–12872PubMedGoogle Scholar
  56. Kulmacz RJ, Lands WE (1985) Stoichiometry and kinetics of the interaction of prostaglandin H synthase with anti-inflammatory agents. J Biol Chem 260:12572–12578PubMedGoogle Scholar
  57. Kurumbail RG, Stevens AM, Gierse JK et al (1996) Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents. Nature 384:644–648PubMedGoogle Scholar
  58. Lecomte M, Laneuville O, Ji C et al (1994) Acetylation of human prostaglandin endoperoxide synthase-2 (cyclooxygenase-2) by aspirin. J Biol Chem 269:13207–13215PubMedGoogle Scholar
  59. Loll PJ, Picot D, Garavito RM (1995) The structural basis of aspirin activity inferred from the crystal structure of inactivated prostaglandin H2 synthase. Nat Struct Biol 2:637–643PubMedGoogle Scholar
  60. Mann B, Gelos M, Siedow A et al (1999) Target genes of beta-catenin-T cell-factor/lymphoid-enhancer-factor signaling in human colorectal carcinomas. Proc Natl Acad Sci U S A 96:1603–1608PubMedGoogle Scholar
  61. Mause SF, Weber C (2010) Microparticles: protagonists of a novel communication network for intercellular information exchange. Circ Res 107:1047–1057PubMedGoogle Scholar
  62. Meade TW, Framework The Medical Research Council’s General Practice Research (1998) Thrombosis prevention trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk. Lancet 351:233–241Google Scholar
  63. Menter DG, Onoda JM, Moilanen D et al (1987) Inhibition by prostacyclin of the tumor cell-induced platelet release reaction and platelet aggregation. J Natl Cancer Inst 78:961–969PubMedGoogle Scholar
  64. Miller JR, Hocking AM, Brown JD et al (1999) Mechanism and function of signal transduction by the Wnt/beta-catenin and Wnt/Ca2+ pathways. Oncogene 18:7860–7872PubMedGoogle Scholar
  65. Minuz P, Fumagalli L, Gaino S et al (2006) Rapid stimulation of tyrosine phosphorylation signals downstream of Gprotein- coupled receptors for thromboxane A2 in human platelets. Biochem J. 400:127–134PubMedGoogle Scholar
  66. Needleman P, Moncada S, Bunting S et al (1976) Identification of an enzyme in platelet microsomes which generates thromboxane A2 from prostaglandin endoperoxides. Nature 261:558–560PubMedGoogle Scholar
  67. Nieswandt B, Hafner M, Echtenacher B et al (1999) Lysis of tumor cells by natural killer cells in mice is impeded by platelets. Cancer Res 59:1295–1300PubMedGoogle Scholar
  68. Okajima F (2002) Plasma lipoproteins behave as carriers of extracellular sphingosine 1-phosphate: is this an atherogenic mediator or an anti-atherogenic mediator? Biochim Biophys Acta 1582:132–137PubMedGoogle Scholar
  69. Pacienza N, Pozner RG, Bianco GA et al (2008) The immunoregulatory glycan-binding protein galectin-1 triggers human platelet activation. FASEB J 22:1113–1123PubMedGoogle Scholar
  70. Padua D, Zhang XH, Wang Q et al (2008) TGFbeta primes breast tumors for lung metastasis seeding through angiopoietin-like 4. Cell 133:66–77PubMedGoogle Scholar
  71. Paganini-Hill A, Chao A, Ross RK et al (1989) Aspirin use and chronic diseases: a cohort study of the elderly. BMJ 299:1247–1250PubMedGoogle Scholar
  72. Pan MR, Chang HC, Hung WC (2008) Non-steroidal anti-inflammatory drugs suppress the ERK signaling pathway via block of Ras/c-Raf interaction and activation of MAP kinase phosphatases. Cell Signal 20:1134–1141PubMedGoogle Scholar
  73. Patrignani P, Filabozzi P, Patrono C (1982) Selective cumulative inhibition of platelet thromboxane production by low-dose aspirin in healthy subjects. J Clin Invest 69:1366–1372PubMedGoogle Scholar
  74. Patrignani P, Panara MR, Greco A et al (1994) Biochemical and pharmacological characterization of the cyclooxygenase activity of human blood prostaglandin endoperoxide synthases. J Pharmacol Exp Ther 271:1705–1712PubMedGoogle Scholar
  75. Patrono C, Baigent C, Hirsh J et al (2008) Antiplatelet drugs: American college of chest physicians evidence-based clinical practice guidelines. Chest 133:199S–233S 8th ednPubMedGoogle Scholar
  76. Patrono C, Ciabattoni G, Patrignani P et al (1985) Clinical pharmacology of platelet cyclooxygenase inhibition. Circulation 72:1177–1184PubMedGoogle Scholar
  77. Patrono C, Ciabattoni G, Pinca E et al (1980) Low dose aspirin and inhibition of thromboxane B2 production in healthy subjects. Thromb Res 17:317–327PubMedGoogle Scholar
  78. Patrono C, García Rodríguez LA, Landolfi R et al (2005) Low-dose aspirin for the prevention of atherothrombosis. N Engl J Med 353:2373–2383PubMedGoogle Scholar
  79. Patrono C, Patrignani P, García Rodríguez LA (2001) Cyclooxygenase-selective inhibition of prostanoid formation: transducing biochemical selectivity into clinical read-outs. J Clin Invest 108:7–13PubMedGoogle Scholar
  80. Pedersen AK, FitzGerald GA (1984) Dose-related kinetics of aspirin: presystemic acetylation of platelet cyclo-oxygenase. N Engl J Med 311:1206–1211PubMedGoogle Scholar
  81. Picot D, Loll PJ, Garavito RM (1994) The X-ray crystal structure of the membrane protein prostaglandin H2 synthase-1. Nature 367:243–249PubMedGoogle Scholar
  82. Pradono P, Tazawa R, Maemondo M et al (2002) Gene transfer of thromboxane A(2) synthase and prostaglandin I(2) synthase antithetically altered tumor angiogenesis and tumor growth. Cancer Res 62:63–66PubMedGoogle Scholar
  83. Prescott SM (2000) Is cyclooxygenase-2 the alpha and the omega in cancer? J Clin Invest 105:1511–1513PubMedGoogle Scholar
  84. Pyne NJ (2010) Pyne S (2010) Sphingosine 1-phosphate and cancer. Nat Rev Cancer 10:489–503PubMedGoogle Scholar
  85. Rimon G, Sidhu RS, Lauver DA et al (2010) Coxibs interfere with the action of aspirin by binding tightly to one monomer of cyclooxygenase-1. Proc Natl Acad Sci USA 107:28–33PubMedGoogle Scholar
  86. Romano M (2006) Lipid mediators: lipoxin and aspirin-triggered 15-epi-lipoxins. Inflamm Allergy Drug Targets 5:81–90PubMedGoogle Scholar
  87. Romano M (2010) Lipoxin and aspirin-triggered lipoxins. Sci World J 10:1048–1064Google Scholar
  88. Roth GJ, Majerus PW (1975) The mechanism of the effect of aspirin on human platelets: 1 acetylation of a particulate fraction protein. J Clin Invest 56:624–632PubMedGoogle Scholar
  89. Roth GJ, Stanford N, Majerus PW (1975) Acetylation of prostaglandin synthase by aspirin. Proc Natl Acad Sci U S A 72:3073–3076PubMedGoogle Scholar
  90. Rothwell PM, Fowkes FG, Belch JF et al (2011) Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet 377:31–41PubMedGoogle Scholar
  91. Rothwell PM, Wilson M, Elwin CE et al (2010) Long-term effect of aspirin on colorectal cancer incidence and mortality: 20 year follow-up of five randomised trials. Lancet 376:1741–1750PubMedGoogle Scholar
  92. Rumble RH, Brooks PM, Roberts MS (1980) Metabolism of salicylate during chronic aspirin therapy. Br J Clin Pharmac 9:41–45Google Scholar
  93. Sandler RS, Halabi S, Baron JA et al (2003) A randomized trial of aspirin to prevent colorectal adenomas in patients with previous colorectal cancer. N Engl J Med 348:883–890PubMedGoogle Scholar
  94. Sciulli MG, Filabozzi P, Tacconelli S et al (2005) Platelet activation in patients with colorectal cancer. Prostaglandins Leukot Essent Fatty Acids 72:79–83PubMedGoogle Scholar
  95. Serhan CN (2005) Lipoxins and aspirin-triggered 15-epi-lipoxins are the first lipid mediators of endogenous anti-inflammation and resolution. Prostaglandins Leukot Essent Fatty Acids 73:141–162PubMedGoogle Scholar
  96. Seymour RA, Rawlins MD (1982) Efficacy and pharmacokinetics of aspirin in post-operative dental pain. J. Clin. Pharmac. 13:807–810Google Scholar
  97. Sharma NP, Dong L, Yuan C et al (2010) Asymmetric acetylation of the cyclooxygenase-2 homodimer by aspirin and its effects on the oxygenation of arachidonic, eicosapentaenoic, and docosahexaenoic acids. Mol Pharmacol 77:979–986PubMedGoogle Scholar
  98. Sharma S, Yang SC, Zhu L et al (2005) Tumor cyclooxygenase-2/prostaglandin E2-dependent promotion of FOXP3 expression and CD4+ CD25+ T regulatory cell activities in lung cancer. Cancer Res 65:5211–5220PubMedGoogle Scholar
  99. Sheehan KM, Sheahan K, O’Donoghue DP et al (1999) The relationship between cyclooxygenase-2 expression and colorectal cancer. JAMA 282:1254–1257PubMedGoogle Scholar
  100. Sidhu RS, Lee JY, Yuan C et al (2010) Comparison of cyclooxygenase-1 crystal structures: cross-talk between monomers comprising cyclooxygenase-1 homodimers. Biochemistry 49:7069–7079PubMedGoogle Scholar
  101. Smith JB, Willis AL (1971) Aspirin selectively inhibits prostaglandin production in human platelets. Nature 231:235–237Google Scholar
  102. Smyth EM, Grosser T, Wang M et al (2009) Prostanoids in health and disease. J Lipid Res 50:S423–S428PubMedGoogle Scholar
  103. Smyth MJH, Dawkins PD (1971) Salicylates and enzyme. J Pharm Pharmacol 23:729–744Google Scholar
  104. Stark LA, Din FV, Zwacka RM et al (2001) Aspirin-induced activation of the NF-kappaB signaling pathway: a novel mechanism for aspirin-mediated apoptosis in colon cancer cells. FASEB J 15:1273–1275PubMedGoogle Scholar
  105. Steinbach G, Lynch PM, Phillips RK et al (2000) The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med 342:1946–1952PubMedGoogle Scholar
  106. Stone E (1763) An account of the success of the bark of the willow tree in the cure of agues. Philos Trans R Soc Lond. 53:195–200Google Scholar
  107. Tani M, Sano T, Ito M et al (2005) Mechanisms of sphingosine and sphingosine 1-phosphate generation in human platelets. J Lipid Res 46:2458–2467PubMedGoogle Scholar
  108. Thun MJ, Henley SJ, Patrono C (2002) Nonsteroidal anti-inflammatory drugs as anticancer agents: mechanistic. Pharmacologic, Clin Issues J Natl Cancer Inst 94:252–266Google Scholar
  109. Topper JN, Cai J, Falb D et al (1996) Identification of vascular endothelial genes differentially responsive to fluid mechanical stimuli: cyclooxygenase-2, manganese superoxide dismutase, and endothelial cell nitric oxide synthase are selectively up-regulated by steady laminar shear stress. PNAS 93:10417–10422PubMedGoogle Scholar
  110. Ulrych T, Böhm A, Polzin   et al (2011) Release of sphingosine-1-phosphate from human platelets is dependent on thromboxane formation. J Thromb Haemost 9:790–798PubMedGoogle Scholar
  111. Vane JR (1971) Inhibition of prostaglandin synthesis as a mechanism of action for Aspirin-like drugs. Nat New Biol 231:232–235PubMedGoogle Scholar
  112. Vane JR, Botting RM (2003) The mechanism of action of aspirin. Thromb Res 110:255–258PubMedGoogle Scholar
  113. Wang D, Dubois RN (2010) Eicosanoids and cancer. Nat Rev Cancer 10:181–193PubMedGoogle Scholar
  114. Weiss HJ, Aledort LM (1967) Impaired platelet-connective-tissue reaction in man after aspirin ingestion. Lancet 2:495–497PubMedGoogle Scholar
  115. Xie W, Chipman JG, Robertson DL et al (1991) Expression of a mitogen-responsive gene encoding prostaglandin synthase is regulated by mRNA splicing. Proc Natl Acad Sci U S A 88:2692–2696PubMedGoogle Scholar
  116. Yin MJ, Yamamoto Y, Gaynor RB (1998) The anti-inflammatory agents aspirin and salicylate inhibit the activity of I(kappa)B kinase-beta. Nature 396:77–80PubMedGoogle Scholar
  117. Yuan C, Rieke CJ, Rimon G et al (2006) Partnering between monomers of cyclooxygenase-2 homodimers. Proc Natl Acad Sci U S A. 103:6142–6147PubMedGoogle Scholar
  118. Yuan C, Sidhu RS, Kuklev DV et al (2009) Cyclooxygenase Allosterism, Fatty Acid-mediated Cross-talk between Monomers of Cyclooxygenase Homodimers. J Biol Chem 284:10046–10055PubMedGoogle Scholar
  119. Zimmermann KC, Waterhouse NJ, Goldstein JC et al (2000) Aspirin induces apoptosis through release of cytochrome c from mitochondria. Neoplasia 2:505–513PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Melania Dovizio
    • 1
  • Annalisa Bruno
    • 2
  • Stefania Tacconelli
    • 1
  • Paola Patrignani
    • 1
  1. 1.Center of Excellence on Aging (CeSI) and Department of Neuroscience and ImagingG. d’Annunzio University, School of MedicineChietiItaly
  2. 2.Center of Excellence on Aging (CeSI) and Department of Medicine and AgingG. d’Annunzio University, School of MedicineChietiItaly

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