Site-selective cyclic AMP analogues are antagonistic to estrogen stimulation of growth and proto-oncogene expression in human breast-cancer cells.
Cyclic AMP (cAMP) analogues that selectively bind to either one of the two binding sites of cAMP-dependent protein kinase demonstrate a potent inhibition of the growth stimulated by estrogen in MCF-7 human breast-cancer cells in culture. The site-selective analogues, which are more potent activators of protein kinase than the analogues studied earlier, exhibit growth inhibition at micromolar concentrations. Among the analogues tested, 8-Cl-cAMP (Site I-selective) and N6-benzyl-cAMP (Site 2-selective) are the 2 most potent inhibitors, causing 40-70% inhibition of the estrogen-stimulated growth at 10-20 microM concentrations with no sign of toxicity. 8-Cl-cAMP (1 microM) in combination with N6-benzyl-cAMP (0.5 microM) almost completely blocks estrogen-stimulated growth, demonstrating synergism between the Site 1- and Site 2-selective analogues. The growth inhibition parallels an increase in the R11 cAMP receptor protein with a decrease in the R1 receptor as well as reduction of c-myc and c-ras oncoproteins, whereas growth inhibition by tamoxifen does not affect the levels of the cAMP receptor proteins or the c-myc and c-ras protein levels. Site-selective cAMP analogues are antagonistic to estrogen stimulation of breast-cancer cell growth through a mechanism different from that of tamoxifen.
Katsaros
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D
Cellular Biochemistry Section, National Cancer Institute, Bethesda, MD 20892.
Ally
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S
Cho-Chung
Y S
YS
D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000031:analogs & derivatives*; D004958:Estradiol / Q000494:pharmacology*; D006801:Humans; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D011519:Proto-Oncogenes; D011953:Receptors, Cyclic AMP / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology; D013997:Time Factors
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D011953:Receptors, Cyclic AMP; D013629:Tamoxifen; D004958:Estradiol; D000242:Cyclic AMP