Inhibition of protein kinase C and calmodulin by the geometric isomers cis- and trans-tamoxifen

O'Brian, C.A., Ioannides, C.G., Ward, N.E. and Liskamp, R.M. (1990) Inhibition of protein kinase C and calmodulin by the geometric isomers cis- and trans-tamoxifen. Biopolymers, 29(1), pp. 97-104. (doi: 10.1002/bip.360290114)

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The triphenylethylene antiestrogen trans-tamoxifen is an effective antitumor agent used in the treatment of human breast cancer. While the antiestrogenic activity of trans-tamoxifen clearly plays an important role in its tumoricidal action, some of the biological effects of trans-tamoxifen are independent of estrogen. Therapeutic concentrations of trans-tamoxifen inhibit protein kinase C (PKC) and calmodulin-dependent enzymes. PKC and calmodulin play critical roles in growth regulation, and there is evidence that inhibition of PKC and calmodulin by trans-tamoxifen may contribute to the antitumor activity of the drug in vivo. The geometric isomers cis- and trans-tamoxifen have a number of opposing biological activities that have been attributed to their interactions with the estrogen receptor. Cis-tamoxifen is generally estrogenic, whereas trans-tamoxifen is generally antiestrogenic. In this report, we compared the effects of cis- and trans-tamoxifen on PKC activity and on calmodulin-dependent cAMP phosphodiesterase activity. Cis- and trans-tamoxifen inhibited the Ca2(+)- and phosphatidylserine- (PS-) dependent activity of purified rat brain PKC with indistinguishable potencies, but cis-tamoxifen was somewhat more potent than the trans isomer in the inhibition of the Ca2(+)- and PS-independent activity of PKC. In addition, cis-tamoxifen was the more potent isomer in the inhibition of T lymphocyte activation, an event that entails a PKC-requiring signal transduction pathway. A modest preference for the cis isomer was also observed in the inhibition of a calmodulin-dependent cAMP phosphodiesterase. These results suggest a congruence between triphenylethylene binding sites on PKC and on the activated calmodulin-cAMP phosphodiesterase complex.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Liskamp, Professor Robert
Authors: O'Brian, C.A., Ioannides, C.G., Ward, N.E., and Liskamp, R.M.
College/School:College of Science and Engineering > School of Chemistry
Journal Name:Biopolymers
ISSN (Online):1097-0282

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