Site selective cyclic amp analogues are antagonistic to estrogen stimulation of growth and proto‐oncogene expression in human breast‐cancer cells

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Abstract
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 micro molar concentrations. Among the analogues tested, 8-CI-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 μM concentrations with no sign of toxicity. 8-CI-cAMP (I μM) in combination with N6-benzyl-cAMP (0.5 μM) 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 R11cAMP receptor protein with a decrease in the R1 receptor as well as a 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.
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