The influence of a novel cyclopropyl antiestrogen (compound 7a) on human breast cancer cells in culture.
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(-5) M, but did not alter the growth of MDA-MB-231 or A-549 cells. The antiproliferative activity of 7a (10(-7) M) on MCF-7 cells was reversed by co-administration of estradiol (10(-8) M). 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(-6) M reduced the length and density of microvilli (MV) on MCF-7 cells, which was reversed by co-administration of estradiol (10(-8) M). 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Jain
P T
PT
Division of Medicinal Chemistry and Pharmacodynamics, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City 73190.
Pento
J T
JT
Magarian
R A
RA
D001943:Breast Neoplasms / Q000473:pathology* / Q000648:ultrastructure; D002455:Cell Division / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology; D008855:Microscopy, Electron, Scanning; D008871:Microvilli / Q000187:drug effects / Q000648:ultrastructure; D011485:Protein Binding / Q000187:drug effects; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D004965:Estrogen Antagonists; D013629:Tamoxifen; C075421:1,1-dichloro-2,3-diphenyl-2-(4-methoxyphenyl)cyclopropane; D004958:Estradiol