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Site selective cyclic amp analogues are antagonistic to estrogen stimulation of growth and proto‐oncogene expression in human breast‐cancer cells
Author(s) -
Katsaros Dionyssios,
Ally Shamsia,
ChoChung Yoon Sang
Publication year - 1988
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.2910410616
Subject(s) - growth inhibition , protein kinase a , estrogen receptor , estrogen , tamoxifen , biology , cell growth , kinase , cancer cell , endocrinology , medicine , chemistry , cancer research , biochemistry , breast cancer , cancer
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 N 6 ‐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 N 6 ‐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 R 11 cAMP receptor protein with a decrease in the R 1 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.