Advertisement

Cancer and Metastasis Reviews

, Volume 19, Issue 1–2, pp 173–179 | Cite as

2-Methoxyestradiol: an Endogenous Antiangiogenic and Antiproliferative Drug Candidate

  • Victor S. Pribluda
  • Edward R. Gubish
  • Edward R. Gubish
  • Theresa M. LaVallee
  • Anthony Treston
  • Glenn M. Swartz
  • Shawn J. Green
Article

Abstract

2-Methoxyestradiol, once considered an inacitve end-metabolite of estradiol, has recently emerged as a very promising agent for cancer treatment. It is orally active in a wide range of tumor models, and inhibits tumor growth at doses showing non clinical signs of toxicity. 2ME2 targets both the tumor cell and endothelial cell compartments by inducing apoptosis in rapidly proliferating cells and inhibiting blood vessel formation at several stages in the angiogenic cascade. Moreover, the ability of 2ME2 to inhibit metastic spread in several models adds to its therapeutic value for cancer treatment at various stages of the disease. Though the mechanism of action is still undefined, several potential molecular targets and pathways of activation have been suggested.

2-methoxyestradiol angiogenesis endothelial cells antiangiogenic therapy cancer steroid 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Pribluda VS, LaVallee TM, Green SJ: In: Tai-Ping D, Fan F and Kohn EC (eds) 2-Methoxyestradiol: A Novel Endogenous Chemotherapeutic and Antiangiogenic in The New Angiotherapy, Human Press Publisher, 2001 (in press)Google Scholar
  2. 2.
    Martucci CP: Metabolic fate of catechol estrogens. In: Merriam GR, Lipsett MB (eds) Catechol Estrogens Raven Press, NY, 1983 pp 115-122Google Scholar
  3. 3.
    Ball P, Haupt M, Knuppen R: Biogenesis and metabolism of catechol estrogens in vitro. In: Merriam GR, Lipsett MB (eds) Catechol Estrogens Raven Press, NY, 1983 pp. 91-104Google Scholar
  4. 4.
    Berg FD, Kuss E: Serum concentration and urinary excretion of 'classical' estrogens, catecholestrogens and 2-methoxyestrogens in normal human pregnancy. Arch Gynecol Obstet 251: 17-27, 1992Google Scholar
  5. 5.
    Dunn JF, Merraim GR, Eil C, Kono S, Loriaux DL, Nisula BC: Testosterone-estradiol binding globulin binds to 2-methoxyestradiol with greater affinity than to testosterone. Clin Endocrinol Metabol 51: 404-406, 1980Google Scholar
  6. 6.
    Fotsis T, Zhang Y, Pepper MS, Adlercreutz H, Montesano R, Nawroth PP, Schweigerer L: The endogeneous oestrogen metabolite 2-methoxyestradiol inhibits angiogenesis and suppresses tumor growth. Nature 368: 237-239, 1994Google Scholar
  7. 7.
    Martucci CP, Fishman J: Impact of continuously administrated catechol estrogens on uterine growth and luteinizing hormone secretion. Endocronology 105: 1288-1292, 1979Google Scholar
  8. 8.
    MacLusky NJ, Barnea ER, Clark CR, Naftolin F: Catechol estrogens and estrogen receptors. In: Merriam GR, Lipsett MB (eds) Catechol Estrogens Raven Press, NY, 1983 pp. 151-166Google Scholar
  9. 9.
    Huober J, Nakamura S, Roth JA, Mukhopadhyay Radiation and 2-methoxyestradiol can cooperate in wild-type p53 human lung cancer cells and induce apoptosis. Proc Am Assoc Canc Res 40, a959, 1999, 144 pp.Google Scholar
  10. 10.
    Amorino GP, Freeman ML, Choy H: Enhancement of radiation effects in vitro by the estrogen metabolite 2-methoxyestradiol. Radiat Res 153: 384-391, 2000Google Scholar
  11. 11.
    Fajardo I, Quesada AR, Nuñez de Castro I, Sánchez-Jiménez F, Medina MA: A comparative study of the effects of genistein and 2-methoxyestradiol on the proteolytic balance and tumor cell proliferation. Brit J Cancer 80: 17-24, 1999Google Scholar
  12. 12.
    Yue T-L, Wang X, Louden CS, Gupta LS, Pillarisetti K, Gu J-L, Hart TK, Lysko PG, Feuerstein GZ: 2-Methoxyestradiol, an endogenous estrogen metabolite induces apoptosis in endothelial cells and inhibits angiogenesis: possible role for stress-activated protein kinase signaling pathway and fas expression. Molecul Pharmacol 51: 951-962, 1997Google Scholar
  13. 13.
    Klauber N, Parangi S, Flynn E, Hamel E, D'Amato RJ: Inhibition of angiogenesis and breast cancer in mice by the microtubule inhibitors 2-methoxyestradiol and Taxol. Cancer Res 57: 81-86, 1997Google Scholar
  14. 14.
    Arbiser JL, Panigrathy D, Klauber N, Rupnick M, Flynn E, Udagawa T, D'Amato R: The antiangiogenic agents TNP-470 and 2-methoxyestradiol inhibit the growth of angiosarcoma in mice. J Am Acad Dermatol 40: 925-929, 1999Google Scholar
  15. 15.
    Wassberg E, Sundel¨of J, Pribluda VS, Green SJ, Hedborg F, Christofferson R: The antiangiogenic and chemotherapeutic natural steroid 2-methoxyestradiol and its derivative 2-propynylestradiol are potent suppressors of neuroblastoma growth when administered orally (submitted for publication)Google Scholar
  16. 16.
    Wassberg E, Hedborg F, Sköldenberg E, Strisdberg M, Christofferson R: Inhibition of angiogenesis induces chromaffin differentiation and apoptosis in neuroblastoma. Am J Pathol 154: 395-403, 1999Google Scholar
  17. 17.
    Pribluda VS, LaVallee TM, Swartz G, Johnson M, Fogler W, Green SJ (manuscript in preparation)Google Scholar
  18. 18.
    Schumacher G, Kataoka M, Roth JA, Mukhopadhyay T: Potent antitumor activity of 2-methoxyestradiol in human pancreatic cancer cell lines. Clin Cancer Res 5: 493-499, 1999Google Scholar
  19. 19.
    Kataoka M, Schumacher G, Cristiano RJ, Atkinson EN, Roth JA, Mukhopadhyay T: An agent that increases tumor suppressor transgene product coupled with systemic transgene delivery inhibits growth of metastatic lung cancer in vivo. Cancer Res 58: 4761-4765, 1998Google Scholar
  20. 20.
    Lottering M-L, de Kock M, Viljoen TC, Grobler CJS, Seegers JC: 17β-estradiol metabolites affect some regulators of the MCF-7 cell cycle. Cancer Lett 110: 181-186, 1996Google Scholar
  21. 21.
    Attalla H, Mäkelä TP, Adlercreutz H, Andersson LC: 2-Methoxyestradiol arrests cells in mitosis without depolymerizing tubulin. Biochem Biophys Res Commun 228: 467-473, 1996Google Scholar
  22. 22.
    Zoubine MN, Weston AP, Johnson DC, Campbell DR, Banerjee SK: 2-Methoxyestradiol-induced growth suppression and lethality in estrogen-responsive MCF-7 cells may be mediated by downregulation of p34cdc2 and cyclin B1 expression. Int J Oncol 15: 639-646, 1999Google Scholar
  23. 23.
    Attalla H, Westberg JA, Andersson LC, Aldercreutz H, Makela TP: 2-Methoxyestradiol-induced phosphorylation of bcl-2: uncoupling from JNK/SAPK activation. Biochem Biophys Res Commun 247: 616-619, 1998Google Scholar
  24. 24.
    D'Amato RJ, Lin CM, Flynn E, Folkman J, Hamel E: 2-Methoxyestradiol, and endogenous mammalian metabolite, inhibits tubulin polymerization by interacting at the colchicine site. Proc Natl Acad Sci USA 91: 3964-3968, 1994Google Scholar
  25. 25.
    Hamel E, Lin CM, Flynn E, D'Amato RJ: Interactions of 2-methoxyestradiol, and endogenous mammalian metabolite, with unploymerized tubulin and with tubulin polymers. Biochemistry 35: 1304-1310, 1996Google Scholar
  26. 26.
    Mukhopadhyay T, Roth JA: Induction of apoptosis in human lung cancer cells after wild-type p53 activation by methoxyestradiol. Oncogene 14: 379-384, 1997Google Scholar
  27. 27.
    Seegers JC, Lottering M-L, Grobler CJS, van Papendorp DH, Habbersett RC, Shou Y, Lehnert BE: The mammalian metabolite, 2-methoxyestradiol, affects p53 levels and apoptosis induction in transformed cells but not in normal cells. J Steroid Biochem Molec Biol 62: 253-267, 1997Google Scholar
  28. 28.
    LaVallee TM, Hembrough WA, Williams MS, Zhan XH, Pribluda VS, Papathanassiu A, Green SJ. 2-Methoxyestradiol upregulates DR5 and induces apoptosis independently of p53. (submitted for publication)Google Scholar
  29. 29.
    Ding VD, Moller DE, Feeney WP, Didolkar V, Nakhla AM, Rhodes L, Rosner W, Smith RG: Sex hormone-binding globulin mediates prostate androgen receptor action via a novel signaling pathway. Endocrinology 139: 213-218, 1998Google Scholar
  30. 30.
    Josefsson E, Tarkowski A: Suppression of type II collagen-induced arthritis by the endogenous estrogen metabolite 2-methoxyestradiol. Arthir Rheum 40: 154-163, 1997Google Scholar
  31. 31.
    Rajan R, Reddy VVR, Reichle F, David JSK, Daly MJ: Effects of catechol estrogen methyl ethers on lipid metabolism in prepubertal rats. Steriods 43: 499-507, 1984Google Scholar
  32. 32.
    Liu D, Bachmann KA: An investigation on the relationship between estrogen, estrogen metabolites and blood cholesterol levels in ovariectomized rats. J Pharmacol Exp Ther 286: 561-568, 1998Google Scholar
  33. 33.
    Turner RT, Evans GL: 2-Methoxyestradiol inhibits longitudinal bone growth in normal female rats. Calcif. Tissue Int 66: 465-469, 2000Google Scholar
  34. 34.
    Yager JD, Liehr JG: Molecular mechanisms of estrogen carcinogenesis. Annu Rev Pharmacol Toxicol 36: 203-232, 1996Google Scholar
  35. 35.
    Liehr JG, Fang WF, Sirbasku DA, Ari-Ulubelen Carcinogenesis of catechol estrogens in Syrian hamsters. J Steroid Biochem 24: 353-356, 1986Google Scholar
  36. 36.
    Purdy RH, Goldzieher JW, Le Quesne PW, Abdel-Baky S, Durocher CK, Moore Jr PH and Rhim JS: Active intermediates and carcinogenesis. In: Merriam GR, Lipsett MB (eds) Catechol Estrogens Raven Press, NY, 1983, pp 123-140Google Scholar
  37. 37.
    Kono S, Merriam GR, Brandon DD, Loraiux DL, Lipsett MB: Radioimmunoassay and metabolism of the catechol estrogen 2-hydroxyestradiol. J Clin Endocrinol Metab 54: 150-154, 1982Google Scholar
  38. 38.
    Longcope C, Femino A, Flood C, Williams, KIH: Metabolic clearance rate and conversion ratios of [3H]2-hydroxyestrone in normal men. J Clin Endocrinol Metab 54: 374-380, 1982Google Scholar
  39. 39.
    McCormick DL, Johnson WD, Pribluda VS, Green SJ, Tomaszewski JE, Smith A: Preclinical development of 2-methoxyestradiol. Proceedings of the American Association for Cancer Research 41, a2080, 2000 328 ppGoogle Scholar
  40. 40.
    Lavigne JA, Helzlsouer KJ, Huang HY, Strickland PT, Bell DA, Selmin O, Watson MA, Hoffman S, Comstock GW, Yager JD: An association between the allele coding for a low activity variant of catechol-O-methyltransferase and the risk for breast cancer. Cancer Res 57: 5493-5497, 1977Google Scholar
  41. 41.
    Pribluda VS, Green SJ: A good estrogen. Science 280: 987-988, 1998Google Scholar
  42. 42.
    Zhu BT, Conney AH: Is 2-methoxyestradiol an endogenous estrogen metabolite that inhibits mammary carcinogenesis? Cancer Res 58: 2269-2277, 1998Google Scholar
  43. 43.
    Kruger EA, Duray PH, Tsokos MG, Venzon DJ, Libutti SK, Dixon SC, Rudek MA, Pluda J, Allegra C, Figg WD: Endostatin inhibits microvessel formation in the ex vivo rat aortic ring angiogenesis assay. Biochem Biophys Res Commun 268: 183-191, 2000Google Scholar

Copyright information

© Kluwer Academic Publishers 2000

Authors and Affiliations

  • Victor S. Pribluda
    • 1
  • Edward R. Gubish
    • 1
  • Edward R. Gubish
    • 1
  • Theresa M. LaVallee
    • 1
  • Anthony Treston
    • 1
  • Glenn M. Swartz
    • 1
  • Shawn J. Green
    • 1
  1. 1.EntreMed Inc.RockvilleUSA

Personalised recommendations