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The influence of a novel cyclopropyl antiestrogen (compound 7a) on human breast cancer cells in culture

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Abstract

Compound 7a ([Z]-1,1,-dichloro-2,3-diphenyl-2-(4-(2-dimethylamino)ethoxy)phenyl) cyclopropane, dihydrogen citrate salt) is a novel cyclopropyl antiestrogen which was shown to be an estrogen antagonist without estrogen agonist activity. The antiproliferative activity of 7a was examined on estrogen receptor (ER)positive MCF-7 and ER-negative MDA-MB-231 human breast cancer cells and A-549 human lung cancer cells. Compound 7a inhibited the growth of MCF-7 cells in a dose-related manner over a concentration range of 10−9 to 10−5M, but did not alter the growth of MDA-MB-231 or A-549 cells. The antiproliferative activity of 7a (10−7M) on MCF-7 cells was reversed by co-administration of estradiol (10−8M). An ER-dependent mechanism of action is also supported by the specific ER binding of 7a in MCF-7 cells observed in this study. A study of cell surface morphology using scanning electron microscopy (SEM) revealed that compound 7a at 10−6M reduced the length and density of microvilli (MV) on MCF-7 cells, which was reversed by co-administration of estradiol (10−8M). Compound 7a did not alter the cell surface morphology of ER-negative MDA-MB-231 cells. In conclusion, 7a inhibited the growth of ER-positive MCF-7 cells in an estradiol-reversible manner, and had no effect on ER-negative MDA-MB-231 cells or A-549 lung cancer cells. The results of this study support the antiestrogenic action of 7a previously observedin vivo and suggest that 7a may be highly effective in the treatment of estrogen-dependent breast cancer and/or in the prophylactic treatment of women with a high risk of breast cancer development.

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References

  1. Robinson SP, Goldestein D, Witt PL, Borden EC, Jordan VC: Inhibition of hormone-dependent and independent breast cancer cell growthin vivo andin vitro with the antiestrogen toremifene and recombinant human interferone-α2. Breast Cancer Res Treat 15: 95–101, 1990

    Google Scholar 

  2. Lerner L, Jordan VC: Development of antiestrogens and their use in breast cancer: Eighth Cain memorial award lecture. Cancer Res 50: 4177–4189, 1990

    Google Scholar 

  3. Furr BJA, Jordan VC: Pharmacology and clinical use of tamoxifen. Pharmacol Ther 25: 127–203, 1984

    Google Scholar 

  4. Love RR, Mazess RB, Barden HS, Epstein S, Newcomb PA, Jordan VC, Carbone PP, DeMets DL: Effects of tamoxifen on bone mineral density in postmenopausal women with breast cancer. New Eng J Med 13: 852–856, 1992

    Google Scholar 

  5. Love RR, Newcomb PA, Wiehe DA, Surawicz TS, Jordan VC, Carbone PP, DeMets DL: Effects of tamoxifen therapy of lipid and lipoprotein levels in postmenopausal patients with node-negative breast cancer. J Natl Cancer Inst 82: 1327–1332, 1990

    Google Scholar 

  6. Fornander T, Cedermark B, Mattsson A, Skoog L, Theve T, Askergren J, Rutqvist LE, Glas U, Silfversward C, Somell A, Wilking N, Hjalmar M: Adjuvant tamoxifen in early breast cancer: occureence of new primary cancers. Lancet i: 117–119, 1989

    Google Scholar 

  7. Boccaardo F, Bruzzi P, Rubagotti A, Nicolo G, Rosso R: Estrogen-like action of tamoxifen on vaginal epithelium in breast cancer patients. Oncology 38: 281–285, 1981

    Google Scholar 

  8. Pento JT, Magarian RA, Wright RJ, King MM, Benjamin EJ: Non-steroidal estrogens and antiestrogens: biological activity of cyclopropyl analogs of stilbene and stilbenediol. J Pharm Sci 70: 399–403, 1981

    Google Scholar 

  9. Day BW, Magarian RA, Jain PT, Pento JT, Mousissian GK, Meyer K: Synthesis and biological evaluation on a series of 1,1-dichloro-2,2,3-triaryl cyclopropanes as pure antiestrogens. J Med Chem 34: 842–851, 1991

    Google Scholar 

  10. Griffin MT, Magarian RA, Jain P, Pento JT, Mousissian GK, Graves DC: Synthesis and biological evaluation of a series of gem-dichlorocyclopropanes as antitumor agents. Anti-Cancer Drug 7: 49–66, 1992

    Google Scholar 

  11. Jain PT, Pento JT, Magarian RA, Graves DC: Antiproliferative activity of a series of cyclopropyl antiestrogens on MCF-7 human breast cancer cells in culture. Anti-Cancer Drugs 2: 487–493, 1991

    Google Scholar 

  12. Jain PT, Pento JT, Magarian RA: Antiestrogenic effects of Z-1, 1-dichloro-2,3-diphenyl-2-(4-methoxyphenyl)cyclopropane(5a) on human breast cancer cells in culture. Anti-Cancer Res 12: 585–590, 1992

    Google Scholar 

  13. Jain PT, Pento JT: Growth medium for the evaluation of antiestrogenic compounds in MCF-7 cell-culture. Meth Find Exptl Pharmacol 13: 595–598, 1991

    Google Scholar 

  14. Jain PT, Pento JT: A vehicle for the evaluation of hydrophobic compounds in cell culture. Res Commun Chem Pathol Pharmacol 74: 105–116, 1991

    Google Scholar 

  15. Jain PT, Pento JT, Graves DC: Cell-growth quantitation methods for the evaluation of antiestrogens in human breast cancer cells in culture. J Pharmacol Tox Meth 27: 203–207, 1992

    Google Scholar 

  16. Stoessel S, Leclercq G: Competitive binding assay for estrogen receptor in monolayer culture: measure of receptor activation potency. J Steroid Biochem 25: 677–682, 1987

    Google Scholar 

  17. Vic P, Vignon F, Derocq D, Rochefort H: Effect of estradiol on the ultrastructure of the growth of MCF-7 cells in culture. Cancer Res 42: 667–673, 1982

    Google Scholar 

  18. Robinson SP, Goldestein D, Witt PL, Borden EC, Jorden VC: Inhibition of hormone dependent and independent breast cancer cell growthin vivo andin vitro with the antiestrogen toremifene and recombinant human interferon-a2. Breast Cancer Res Treat 15: 95–101, 1990

    Google Scholar 

  19. Sutherland RK, Hall RE, Taylor IW: Cell proliferation kinetics of MCF-7 human breast carcinoma cells in culture and effect of tamoxifen on exponentially growing and plateauphase. Cancer Res 43: 3998–4006, 1983

    Google Scholar 

  20. Bardon S, Vignon F, Derocq D, Rochefort H: The antiproliferative effect of tamoxifen in breast cancer cells: mediation by the estrogen receptor. Mol Cell Endocrinol 35: 89–96, 1984

    Google Scholar 

  21. Buttler WB, Kelsey WH, Goran N: Effect of serum and insulin on the sensitivity of the human breast cancer cell-line MCF-7 to estrogen and antiestrogen. Cancer Res 41: 82–88, 1981

    Google Scholar 

  22. Edwards DP, Adams DJ, McGuire WL: Estrogen regulation of growth and specific protein synthesis in human breast cancer cells in tissue culture. Adv Exp Med Biol 138: 133–149, 1982

    Google Scholar 

  23. Briand P, Lykkesfeldt AE: Effect of estrogen and antiestrogen on the human breast cancer cell line MCF-7 adapted to growth at low serum concentration. Cancer Res 44: 1114–1119, 1984

    Google Scholar 

  24. Lippman ME, Bolan G, Huff K: The effects of estrogens and antiestrogens on hormone responsive human breast cancer cells in long-term tissue culture. Cancer Res 36: 4595–4601, 1976

    Google Scholar 

  25. McGuire WL, Horwitz KB, Zava DT, Garola RE, Chamness GC: Hormones in breast cancer: update 1978. Metab Clin Exp 27: 487–501, 1978

    Google Scholar 

  26. Nawata H, Chong MT, Bronzert D, Lippman ME: Estradiolindependent growth of a subline of MCF-7 human breast cancer cells in culture. J Biol Chem 256: 6895–6902, 1981

    Google Scholar 

  27. Katzenellenbogen KS, Norman MJ, Eckert RL, Peltz SW, Mangel WF: Bioactivities, estrogen receptor interactions, and plasminogen activator-induced activities of tamoxifen and hydroxytamoxifen isomers in MCF-7 human breast cancer cells. Cancer Res 44: 112–119, 1984

    Google Scholar 

  28. Wakeling AE, Bowler J: Novel antiestrogens without partial agonist activity. J Steroid Biochem 31: 645–653, 1988

    Google Scholar 

  29. Russo J, Bradley RH, McGrath C, Russo IH: Scanning and transmission electron microscopy study of human breast carcinoma cell line (MCF-7) cultured in collagen-coated cellulose sponge. Cancer Res 37: 2004–2014, 1977

    Google Scholar 

  30. Antalky T, Pelletier G, Zeytinoglu F, Labrie F: Changes of morphology and prolactin secretion induced by 2-Br-α-ergocryptine estradiol and thyrotropin-releasing hormone in rat anterior pituitary cells in culture. J Cell Biol 86: 377–387, 1980

    Google Scholar 

  31. Porter KR, Fonte VG: Observations on topography of normal and cancer cells. Scanning Electron Microsc 6: 686–688, 1973

    Google Scholar 

  32. Yates J, King RJB: Correlation of growth properties and morphology with hormone responsiveness of mammary tumor cells in culture. Cancer Res 41: 258–262, 1981

    Google Scholar 

  33. King MM, Pento JT, Magarian RA, Brueggemann G: The interaction of dietary fat and antiestrogen treatment on DMBA-induced mammary tumors in the rat. Nutr Cancer 7: 239–249, 1985

    Google Scholar 

  34. King MM, Magarian RA, Terao J, Brueggmann G: Effect of nonsteroidal antiestrogen, Analog II and tamoxifen on a metastatic transplantable rat mammary tumors. J Natl Cancer Inst 74: 447–451, 1985

    Google Scholar 

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  1. Pramod T. Jain

    Present address: Dept. of Pathology, College of Medicine, University of Maryland, 10 S. Pine St., 21201, Baltimore, MD, USA

Authors and Affiliations

  1. Division of Medicinal Chemistry and Pharmacodynamics, College of Pharmacy, Univ. of Oklahoma Health Sciences Center, 1110 N Stonewall, 73190, Oklahoma City, OK, USA

    Pramod T. Jain, J. Thomas Pento & Robert A. Magarian

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  1. Pramod T. Jain
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  2. J. Thomas Pento
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  3. Robert A. Magarian
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Jain, P.T., Pento, J.T. & Magarian, R.A. The influence of a novel cyclopropyl antiestrogen (compound 7a) on human breast cancer cells in culture. Breast Cancer Res Tr 25, 225–233 (1993). https://doi.org/10.1007/BF00689837

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