Cancer and Metastasis Reviews

, Volume 13, Issue 3–4, pp 349–364 | Cite as

Prostacyclin and its analogues: antimetastatic effects and mechanisms of action

  • Martin R. Schneider
  • Dean G. Tang
  • Michael Schirner
  • Kenneth V. Honn
Article

Abstract

More than a decade ago, prostacyclin, a dienoic bicyclic eicosanoid derived from the metabolism of arachidnoic acid, was found to possess potent inhibitory effects on tumor cell metastasis. Thereafter, several laboratories demonstrated the metastasis-suppressive activity of prostacyclin in a wide spectrum of tumor types. Due to the short half-life of prostacyclin, researchers have focused on looking for stable prostacyclin analogues which have extended half lives and increased bioavailabilities. Cicaprost, among other prostacyclin analogues tested, has been demonstrated, like prostacyclin, to effectively inhibit metastasis in several different animal models (i.e., both experimental and spontaneous metastasis models). Prostacyclin as well as cicaprost prevent not only hematogenous, but also lymphatic metastasis. Furthermore, these compounds also inhibit the growth of established micrometastases after removal of the primary tumors. Mechanistic studies revealed that the antimetastatic effects of prostacyclin and its analogues are more related to their interference with tumor cell-host interactions (such as tumor cell induced platelet aggregation, tumor cell adhesion to endothelial cells and subendothelial matrix, tumor cell induced endothelial cell retraction, etc.) than their direct inhibition of the growth of primary tumors. The potent and widespread metastasis-retarding effects of prostacyclin and its stable analogues in animal tumor models warrant their clinical trial in treating human cancer patients and preventing metastasis.

Key words

prostacyclin metastasis cicaprost platelet 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Abecassis JR, Millon-Collard C, Cazenave J: Adhesion of human breast cancer cell line MCF-7 to human vascular endothelial cells in culture. Enhancement by activated platelets. Int J Cancer 40: 525–531, 1987Google Scholar
  2. 2.
    Costantini V, Fuschiotti P, Giampietri N, Allegrucci M, Agnelli G, Nenci GG, Fioretti M: Effects of a stable prostacyclin analogue on platelet activity and on host immunocompetence in mice. Prostaglandins 39: 581–599, 1990Google Scholar
  3. 3.
    Costantini V, Fuschiotti P, Allegrucci M, Agnelli G, Nenci GG, Fioretti M: Platelet-tumor cell interaction: effect of prostacyclin and a synthetic analog on metastasis formation. Cancer Chemother Pharmacol 22: 289–293, 1988Google Scholar
  4. 4.
    Crutchley DJ, Hirsh MJ: The stable prostacyclin analog, iloprost, and prostaglandin E1 inhibit monocyte procoagulant activityin vitro. Blood 77: 382–386, 1991Google Scholar
  5. 5.
    Dejana E, Bertochi F, Bortolami MC, Regonesi A, Tonta A, Breviarion P, Giavazzi R: Interleukin 1 promotes tumor cell adhesion to cultured endothelial cells. J Clin Invest 82: 1466–1470, 1988Google Scholar
  6. 6.
    Dunning WF: Prostate cancer in the rat. Natl Cancer Inst Monogr 12: 351–369, 1963Google Scholar
  7. 7.
    Giraldi T, Rapozzi V, Perissin L, Zorzet S: Antimetastatic action in mice of PG12 analog iloprost. In: Honn KV, Marnett LJ, Nigam S, Walden T (eds) Eicosanoids and Other Bioactive Lipids in Cancer and Radiation Injury. Kluwer Academic Publishers, Boston, 1990, pp 415–418Google Scholar
  8. 8.
    Graf H: personal communicationGoogle Scholar
  9. 9.
    Gorelik E, Bere WW, Herbemlan RB: Role of NK cells in antimetastatic effect of anticoagulant drugs. Int J Cancer 33: 87–94, 1984Google Scholar
  10. 10.
    Hart IR, Talmadge J, Fidler IJ: Metastatic behavior of a murine reticulum cell sarcoma exhibiting organ-specific growth. Cancer Res 41: 1281–1287, 1981Google Scholar
  11. 11.
    Hildebrand M, Staks T, Nieweboer: Pharmacokinetics and pharmacodynamics of cicaprost in healthy volunteers after oral administration of 5 to 20 mcg. Eur J Clin Pharmacol 39: 149–153, 1990Google Scholar
  12. 12.
    Honn KV, Busse WD, Sloane BF: Prostacyclin and thromboxanes. Implications for their role in tumor cell metastasis. Biochem Pharmacol 32: 1–11, 1983Google Scholar
  13. 13.
    Honn KV, Cicone B, Skoff A: Prostacyclin: a potent antimetastatic agent. Science 212: 1270–1272, 1981Google Scholar
  14. 14.
    Honn KV, Onoda JM, Menter DG, Cavanaugh P, Taylor JD, Crissman J, Ryan RE, Sloane BF: Possible strategies for antimetaslastic therapy. Prog Clin Biol Res 212: 217–249, 1986Google Scholar
  15. 15.
    Honn KV, Sloane BF: Prostacyclin, thromboxanes, and hematogenous metastasis. Prostaglandin Thromboxane Leukotiene Res 12: 313–318, 1983Google Scholar
  16. 16.
    Honn KV, Tang DG, Chen YQ: Platelets and cancer metastasis: More than an epiphenomenon. Seminar Thromb Hemost 18: 392–415, 1992Google Scholar
  17. 17.
    Honn KV: Inhibition of tumor cell metastasis by modulation of the vascular prostacyclin/thromboxane A2 system. Clin Exp Metastasis 1: 103–114, 1983Google Scholar
  18. 18.
    Isaacs JT, Wake N, Coffey DS, Sandberg AA: Genetic instability coupled to clonal selection as a mechanism for tumor progression in the Dunning R3327 rat prostatic adenocarcinoma system. Cancer Res 42: 2353–2361, 1982Google Scholar
  19. 19.
    Ito S, Hashimoto H, Negishi M, Suzuki M, Koyano H, Noyori R, Ichikawa A: Identification of the prostacyclin receptor by use of [15-3H1] 19-(3-acidophenyl)-20-norisocarbacyclin, an irreversible specific photoaffinity probe. J Biol Chem 267: 20326–2033, 1992Google Scholar
  20. 20.
    Karpatkin S, Ambrogio C, Pearlstern E: Lack of effect ofin vivo prostacyclin on the development of pulmonary metastases in mice following intravenous injection of CT26 colon carcinoma, Lewis lung carcinoma, or B16 amelanotic melanoma cells. Cancer Res 44: 3880–3883, 1984Google Scholar
  21. 21.
    Kato S, Kobari M, Matsuno S, Sato T: Inhibitory effect of anti-platelet prostaglandin on liver metastasis of hamster pancreatic cells. Nippon Geka Gakkai Zasski 90: 745–752, 1989Google Scholar
  22. 22.
    Kim U, Baumler A, CalTuthers M, Bielat K: Immunological escape mechanism in spontaneously metastasizing mammary tumors. Proc Natl Acad Sci USA 72: 1012–1016, 1975Google Scholar
  23. 23.
    Kim U: Pathogenesis and characteristics of spontaneously metastasizing carcinoma and general principle of metastasis. J Surg Oncol 33: 151–165, 1986Google Scholar
  24. 24.
    Lapis K, Timar T, Papay J, Paku S, Szende B, Ladanyi A: Experimental metastasis inhibition by pretreatment of the host. Arch Geschwulstforsch 60: 97–102, 1990Google Scholar
  25. 25.
    Maat B, Hilgard P: Anticoagulants and metastases evaluation of antimetastatic effects in different model systems. J Cancer Res Clin Oncol 101: 275–283, 1981Google Scholar
  26. 26.
    Mahalingam M, Ugen K, Kao KJ, Klern PA: Functional role of platelets in experimental metastasis studied with cloned murine fibrosarcoma cell variants. Cancer Res 48: 1460–1464, 1988Google Scholar
  27. 27.
    Menter DG, Harkins C, Onoda J, Riorden W, Sloane BF, Taylor JD, Honn KV: Inhibition of tumor cell induced platelet aggregation by prostacyclin and carbacyclin: an ultrastructural study. Invasion Metastasis 7: 109–128, 1987Google Scholar
  28. 28.
    Menter DG, Onoda M, Moilanen D, Sloane BF, Taylor JD, Honn KV: Inhibition by prostacyclin of the tumor cell-induced platelet release reaction and platelet aggregation. J Natl Cancer Inst 78: 961–969, 1987Google Scholar
  29. 29.
    Menter DG, Onoda JM, Taylor JD, Honn KV: Effects of prostacyclin on tumor cell-induced platelet aggregation. Cancer Res 44: 450–456, 1984Google Scholar
  30. 30.
    Moncada S, Gryglewski G, Bunting S, Vane JR: An enzyme isolated from arteries transforms prostaglandin peroxides to an instable substance that inhibits platelet aggregation. Nature 263: 663–665, 1976Google Scholar
  31. 31.
    Muller B, Schmidtke T, Witt W: Adherence of leukocytes to electrically damaged venules. Eicosanoids 1: 13–17, 1988Google Scholar
  32. 32.
    Niitsu Y, Ishigaki S, Kogawa K, Mogi Y, Watanabe N, Kohgo Y, Urushizaki I: Effect of combined administration of a prostacyclin analogue and adriamycin against the artificial metastasis of Meth A cell. Invasion Metastasis 8: 57–72, 1988Google Scholar
  33. 33.
    Paubert-Braquet M, Picquot S, Boichot-La G, Schneider M, Bourgan R: Cicaprost regulates endothelial/circulating cells cross talk via a modulation of IL-1 and IL-6 production and of ICAM, VCAM and ELAM expression. Pharmacologist 34: 167, 1992Google Scholar
  34. 34.
    Riemann D: personal communicationGoogle Scholar
  35. 35.
    Saiki I, Fujii H, Yoneda J, Abe F, Nakajima M, Tsuruo T, Azuma I: Role of aminopeptidase N (CD 13) in tumor-cell invasion and extracellular matrix degradation. Int J Cancer 54: 137–143, 1993Google Scholar
  36. 36.
    Sava G, Perissin L, Zorzet S, Piccini P, Giraldi T: Antimetastatic action of the prostacyclin analog iloprost in the mouse. Clin Exp Metastasis 7: 671–678, 1989Google Scholar
  37. 37.
    Schirner M, Schneider MR: Inhibition of metastasis in rats with established SMT2A mammary carcinoma growth. J Cancer Detect Prev 1994, in pressGoogle Scholar
  38. 38.
    Schirner M, Schneider MR: Cicaprost inhibits metastasis of animal tumors. Prostaglandins 42: 461, 1991Google Scholar
  39. 39.
    Schirner M, Schneider MR: The stable prostacyclin analogue Cicaprost inhibits metastasis of R3327 MAT Lu prostate carcinoma and SMT 2A mammary carcinoma. J Cancer Res Clin Oncol 118: 497–450, 1992Google Scholar
  40. 40.
    Schirner M, Lichtner RB, Graf H, Schneider MR: Efficacy of cicaprost on metastasis in advanced tumor disease, 1994, in pressGoogle Scholar
  41. 41.
    Schirner M, Schneider MR: Cicaprost does not affect tumor inhibitory potential of cytostatic drugs. Anticancer Research 13: 743–746, 1993Google Scholar
  42. 42.
    Schneider MR, Schirner M: Antimetastatic prostacyclin analogs. Drugs Future 18: 29–48, 1993Google Scholar
  43. 43.
    Schirner M, Lichtner RB, Schneider MR: The stable prostacyclin analogue Cicaprost inhibits metastasis to lungs and lymph nodes in the 13762NF MTLn3 rat mammary carcinoma. Clin Exp Metastasis 12: 24–30, 1994Google Scholar
  44. 44.
    Schwalke M, Tzanakakis M, Vezeridis MP: Effects of prostacyclin on hepatic metastases from human pancreatic cancer in the nude mouse. J Surg Res 49: 164–167, 1990Google Scholar
  45. 45.
    Skuballa W, Schafer M: Prostacyclin-Derivate. Nachr Chem Tech Lab 37: 584–590, 1989Google Scholar
  46. 46.
    Tang DG, Diglio CA, Honn KV: 12(S)-HETE-induced microvascular endothelial cell retraction results from PKC-dependent rearrangement of cytoskeletal elements and alpha V beta 3 integrins. Prostaglandins 45: 249–267, 1993Google Scholar
  47. 47.
    Tang DG, Grossi IM, Chen YQ, Diglio CA, Honn KV: 12(S)-HETE promotes tumor-cell adhesion by increasing surface expression of αvβ3 integrins on endothelial cells. Int J Cancer 54: 102–111, 1993Google Scholar
  48. 48.
    Tang DG, Onoda JM, Steinert B, Grossi IM, Nelson KK, Umbarger L, Diglio CA, Taylor JD, Honn KV: Phenotypic properties of cultured tumor cells: integrin αIIbβ3 expression, tumor-cell-induced platelet aggregation, and tumorcell adhesion to endothelium as important parameters of experimental metastasis. Int J Cancer 54: 338–347, 1993Google Scholar
  49. 49.
    Thierauch K-H, Dinter H, Stock G: Prostaglandins and their receptors: II. J Hypertension, 1994, in pressGoogle Scholar
  50. 50.
    Tzanakakis GN, Agarwal KC, Vezeridis MP: Inhibition of hepatic metastasis from a human pancreatic adenocarcinoma RWP-2 in the nude mouse by prostacyclin, forskolin and ketokonazol. Cancer 65: 446–451, 1990Google Scholar
  51. 51.
    Ushikubi F, Nakajima M, Hirata M, Okuma M, Fujiwara M, Narumiya S: Purification of the thromboxane A2/prostaglandin H2 receptor for human blood platelets. J Biol Chem 264: 16496, 1989Google Scholar
  52. 52.
    Namba T, Oida H, Sugimoto Y, Kakizuka A, Negishi M, Ichikawa A, Narumiya S: cDNA cloning of a mouse prostacyclin receptor. Multiple signaling pathways and expression in thymic medulla. J Biol Chem 269: 9986–9993, 1994Google Scholar
  53. 53.
    Tsuruo T, Watanabe M, Oh-hara T: Stimulation of the growth of metastatic clones of mouse colon adenocarcinoma 26in vitro by platelet-derived growth factor. Jpn J Cancer Res 80: 136–140, 1989Google Scholar
  54. 54.
    Orr FW, Miller BW, Singh G: Chemotactic activity of bone and platelet-derived TGF-beta for bone-metastasizing rat Walker 256 carcinoma cells. Invasion Metastasis 10: 241–252, 1990Google Scholar
  55. 55.
    Lewalle JM, Castronovo V, Goffinet G, Foidart JM: Malignant cell attachment to endothelium ofex vivo perfused human umbilical vein. Modulation by platelets, plasma and fibronectin. Thromb Res 62: 287–298, 1991Google Scholar
  56. 56.
    Grossi IM, Fitzgerald LA, Umbarger LA, Nelson KK, Diglio CA, Honn KV: Bidirectional control of membrane expression and/or activation of the tumor cell IGRpIIb/IIIa receptor and tumor cell adhesion by lipoxygenase products of arachidonic acid and linoleic acid. Cancer Res 49: 1029–1037, 1989Google Scholar
  57. 57.
    Mentor DG, Sloane BF, Steinert BW, Onoda JM, Craig C, Harkins C, Taylor JD, Honn KV: Platelet enhancement of tumor cell adhesion to subendothelial matrix: Role of platelet cytoskeleton and platelet membrane. J Natl Cancer Inst 79: 1077–1090, 1987Google Scholar
  58. 58.
    Mentor DG, Steinert BW, Sloane BF, Gundlach N, O'Gara CY, Marnett LJ, Diglio CA, Walz D, Taylor JD, Honn KV: Role of platelet membrane in enhancement of tumor cell adhesion to endothelial cell extracellular matrix. Cancer Res 47: 6751–6762, 1987Google Scholar
  59. 59.
    Timar J, Chen YQ, Liu B, Bazaz R, Taylor JD, Honn KV: The lipoxygenase metabolite 12(S)-HETE promotes αIIbβ3 integrin-mediated tumor cell spreading on fibronectin. Int J Cancer 52: 594–603, 1992Google Scholar
  60. 60.
    Honn KV, Tang DG, Grossi IM, Renaud C, Duniec ZM, Johnson CR, Diglio CA: Enhanced endothelial cell retration mediated by 12(S)-HETE: A proposed mechanism for the role of platelets in tumor cell metastasis. Exp Cell Res 210: 1–9, 1994Google Scholar
  61. 61.
    Honn KV, Grossi IM, Diglio CA, Wojtukiewicz M, Taylor JD: Enhanced tumor cell adhesion to the subendothelial matrix resulting from 12(S)-HETE-induced endothelial cell retraction. FASEB J 3: 2285–2293, 1989Google Scholar
  62. 62.
    Honn KV, Meyer J: Thromboxane and prostacyclin: Positive and negative modulators of tumor growth. Biochem Biophys Res Commun 102: 1122–1129, 1981Google Scholar
  63. 63.
    Tang DG, Grossi IM, Tang KQ, Honn KV: Prostacyclin and its stable analogue cicaprost inhibit tumor cell invasion and TPA and 12(S)-HETE enhanced tumor cell adhesion. SubmittedGoogle Scholar
  64. 64.
    Honn KV, Nelson KK, Renaud C, Bazaz R, Diglio CA, Timar J: Fatty acid modulation of tumor cell adhesion to microvessel endothelium and experimental metastasis. prostaglandins 44: 413–429, 1992Google Scholar
  65. 65.
    Liu B, Timar J, Howlett J, Diglio CA, Honn KV: Lipoxygenase metabolites of arachidonic and linoleic acids modulate the adhesion of tumor cells to endothelium via regulation of protein kinase C. Cell Regul 2: 1045–1055, 1991Google Scholar
  66. 66.
    Honn KV, Grossi IM, Chang YS, Chen Y: Lipoxygenases, integrin receptors, and metastasis. In: Honn KV, Nigam S, Marnett LJ, Walden T (eds) Eicosanoids and Other Bioactive Lipids in Cancer and Radiation Injury. Kluwer Academic Publishers, Boston, 1991, pp 321–329Google Scholar
  67. 67.
    Honn KV, Tang DG, Grossi IM, Duniec ZM, Timar J, Renaud C, Leithauser M, Blair I, Johnson CR, Diglio CA, Kimler VA, Taylor JD, Marnett LJ: Tumor cell-derived 12(S)-hydroxyeicosatetraenoic acid induces microvascular endothelial cell retraction. Cancer Res 54: 565–574, 1994Google Scholar
  68. 68.
    Grossi IM, Diglio CA, Honn KV: Control of tumor cell induced endothelial cell retraction by lipoxygenase metabolites, prostacyclin and prostacyclin analogues. In: Honn KV, Nigam S, Marnett LJ, Walden T (eds) Eicosanoids and Other Bioactive Lipids in Cancer and Radiation Injury. Kluwer Academic Publishers, Boston, 1991, pp 410–414Google Scholar
  69. 69.
    Honn KV, Grossi IM, Timar J, Chopra H, Taylor JD: Platelets and cancer metastasis. In: Orr FW, Buchanan M, Weiss L (eds) Microcirculation in Cancer Metastasis. CRC Press, Boca Raton, FL, 1991, pp 42–62Google Scholar

Copyright information

© Kluwer Academic Publishers 1994

Authors and Affiliations

  • Martin R. Schneider
    • 1
  • Dean G. Tang
    • 2
  • Michael Schirner
    • 1
  • Kenneth V. Honn
    • 2
    • 3
    • 4
    • 5
  1. 1.Research Laboratories of Schering AGBerlinGermany
  2. 2.Departments of Radiation OncologyWayne State UniversityDetroitUSA
  3. 3.Departments of ChemistryWayne State UniversityDetroitUSA
  4. 4.Departments of PathologyWayne State UniversityDetroitUSA
  5. 5.Gershenson Radiation Oncology CenterHarper HospitalDetroitUSA

Personalised recommendations