Antiestrogenic Potency and Binding Characteristics of the Triphenylethylene H1285 in MCF-7 Human Breast Cancer Cells

Yhun Yhong Sheen, Thomas S. Ruh, Walter F. Mangel, Benita S Katzenellenbogen

Research output: Contribution to journalArticle

Abstract

The antiestrogenic character and potency of 4-(N,N-diethylam-inoethoxy )-4'-methoxy-α -(p-hydroxypheny l)-α'-ethyIstilbene (H1285) and its binding to estrogen receptor and to estrogen-noncompetible antiestrogen binding sites have been studied in MCF-7 human breast cancer cells. H1285 has an affinity for the estrogen receptor (K d 0.23 nM) which is comparable to that of estradiol (K d 0.25 nM), and the binding of these two compounds to estrogen receptor is mutually competitive. On high salt sucrose gradients, the sedimentation profiles of nuclear receptor complexes with H1285 and estradiol are different. While the sedimentation profile of the complex with estradiol varies with the buffer composition, being 4.1 S in phosphate:thioglycerol: glycerol and predominantly 5.5S in Tris:EDTA buffered gradients, the H1285 receptor complex shows the same sedimentation (5.5S) regardless of the buffer composition. H1285 also binds to estrogen-noncompetable antiestrogen binding sites that are distinct from the estrogen receptor with a low affinity, only 15% that of the antiestrogen tamoxifen. The biological character and potency of Hf285 were examined by determining its effects on cell proliferation, cellular progesterone receptor levels, and plasminogen activator activity. In MCF-7 cells, H1285 was a 30-to 100-fold more potent inhibitor of cell proliferation than was the antiestrogen tamoxifen, and it was approximately equipotent with the higher affinity antiestrogen trans-hydroxytamoxifen. H1285 evoked very minimal increases in cellular progesterone receptor levels, and no increase in plasminogen activator activity over a broad range of concentrations (10 -10 -10 -6 M), and it suppressed plasminogen activator activity stimulated by estradiol. Therefore, by the criteria we have used, we conclude that H1285 is a potent and very effective antiestrogen in MCF-7 cells. The ability of estradiol to reverse the suppression of cell proliferation by H1285, and the high affinity of H1285 for estrogen receptor and its low affinity for estrogen-noncompetible antiestrogen binding sites suggest that H1285 exerts its antiestrogenic effects via interaction with the estrogen receptor of these breast cancer cells.

Original languageEnglish (US)
Pages (from-to)4192-4199
Number of pages8
JournalCancer Research
Volume45
Issue number9
StatePublished - Sep 1 1985

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Estrogen Receptor Modulators
Breast Neoplasms
Estrogen Receptors
Estradiol
Plasminogen Activators
Estrogens
Binding Sites
MCF-7 Cells
Cell Proliferation
Progesterone Receptors
Tamoxifen
Buffers
triphenylethylene
H 1285
Cytoplasmic and Nuclear Receptors
Edetic Acid
Glycerol
Sucrose
Salts
Phosphates

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Antiestrogenic Potency and Binding Characteristics of the Triphenylethylene H1285 in MCF-7 Human Breast Cancer Cells. / Sheen, Yhun Yhong; Ruh, Thomas S.; Mangel, Walter F.; Katzenellenbogen, Benita S.

In: Cancer Research, Vol. 45, No. 9, 01.09.1985, p. 4192-4199.

Research output: Contribution to journalArticle

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abstract = "The antiestrogenic character and potency of 4-(N,N-diethylam-inoethoxy )-4'-methoxy-α -(p-hydroxypheny l)-α'-ethyIstilbene (H1285) and its binding to estrogen receptor and to estrogen-noncompetible antiestrogen binding sites have been studied in MCF-7 human breast cancer cells. H1285 has an affinity for the estrogen receptor (K d 0.23 nM) which is comparable to that of estradiol (K d 0.25 nM), and the binding of these two compounds to estrogen receptor is mutually competitive. On high salt sucrose gradients, the sedimentation profiles of nuclear receptor complexes with H1285 and estradiol are different. While the sedimentation profile of the complex with estradiol varies with the buffer composition, being 4.1 S in phosphate:thioglycerol: glycerol and predominantly 5.5S in Tris:EDTA buffered gradients, the H1285 receptor complex shows the same sedimentation (5.5S) regardless of the buffer composition. H1285 also binds to estrogen-noncompetable antiestrogen binding sites that are distinct from the estrogen receptor with a low affinity, only 15{\%} that of the antiestrogen tamoxifen. The biological character and potency of Hf285 were examined by determining its effects on cell proliferation, cellular progesterone receptor levels, and plasminogen activator activity. In MCF-7 cells, H1285 was a 30-to 100-fold more potent inhibitor of cell proliferation than was the antiestrogen tamoxifen, and it was approximately equipotent with the higher affinity antiestrogen trans-hydroxytamoxifen. H1285 evoked very minimal increases in cellular progesterone receptor levels, and no increase in plasminogen activator activity over a broad range of concentrations (10 -10 -10 -6 M), and it suppressed plasminogen activator activity stimulated by estradiol. Therefore, by the criteria we have used, we conclude that H1285 is a potent and very effective antiestrogen in MCF-7 cells. The ability of estradiol to reverse the suppression of cell proliferation by H1285, and the high affinity of H1285 for estrogen receptor and its low affinity for estrogen-noncompetible antiestrogen binding sites suggest that H1285 exerts its antiestrogenic effects via interaction with the estrogen receptor of these breast cancer cells.",
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