Triphenylethylenes: a new class of protein kinase C inhibitors

O'Brian, C.A., Liskamp, R.M. , Solomon, D.H. and Weinstein, I.B. (1986) Triphenylethylenes: a new class of protein kinase C inhibitors. Journal of the National Cancer Institute, 76(6), pp. 1243-1246. (doi: 10.1093/jnci/76.6.1243)

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The Ca2+- and phospholipid-dependent phosphotransferase activity of protein kinase C was inhibited by the triphenylethylene compounds clomiphene [drug concentration causing 50% inhibition (IC50) = 25 microM], 4-hydroxytamoxifen (IC50 = 25 microM), and N-desmethyltamoxifen (IC50 = 8 microM). The Ca2+- and phospholipid-independent phosphorylation of protamine sulfate, which is catalyzed by protein kinase C, was not inhibited by the triphenylethylenes, suggesting that they do not interact directly with the active site of protein kinase C. The inhibitory potency of each triphenylethylene was reduced when the phospholipid concentration was increased, providing evidence that these drugs inhibited protein kinase C by interacting with phospholipids. The potencies of the effects of the triphenylethylenes on protein kinase C in the lipid environment of intact cells were evaluated by determining their efficacies in the inhibition of [3H]phorbol 12,13-dibutyrate (PDBu) binding to mouse embryo C3H/10T1/2 cells. Micromolar concentrations of each drug inhibited [3H]PDBu binding in these cells. N-Desmethyltamoxifen, 4-hydroxytamoxifen, and tamoxifen inhibited protein kinase C with the same order of potency as that which has been reported for their inhibition of MCF-7 cell growth by Reddel et al. (1983). N-Desmethyltamoxifen and 4-hydroxytamoxifen were also more potent than tamoxifen in the inhibition of the growth of mouse embryo fibroblast C3H/10T1/2 cells. These correlations suggest that the mechanism of growth inhibition by tamoxifen and its metabolites includes interactions with protein kinase C.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Liskamp, Professor Robert
Authors: O'Brian, C.A., Liskamp, R.M., Solomon, D.H., and Weinstein, I.B.
College/School:College of Science and Engineering > School of Chemistry
Journal Name:Journal of the National Cancer Institute
ISSN (Online):1460-2105

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