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Inhibition of protein kinase C and calmodulin by the geometric isomers cis ‐ and trans ‐tamoxifen
Author(s) -
O'Brian Catherine A.,
Ioannides Constantin G.,
Ward Nancy E.,
Liskamp Rob M.
Publication year - 1990
Publication title -
biopolymers
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.556
H-Index - 125
eISSN - 1097-0282
pISSN - 0006-3525
DOI - 10.1002/bip.360290114
Subject(s) - tamoxifen , antiestrogen , protein kinase c , chemistry , calmodulin , signal transduction , cis–trans isomerism , protein kinase a , pharmacology , kinase , biochemistry , enzyme , medicine , stereochemistry , biology , breast cancer , cancer
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 antiumor 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 Ca 2+ ‐ 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 Ca 2+ ‐ 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 of 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. We conclude that the interactions of cis ‐ and trans ‐tamoxifen with PKC and the activated calmodulin–cAMP phosphodiesterase complex offer a criterion for distinguishing biological effects of triphenylethylenes that are due to interactions with the estrogen receptor from the biological effects resulting from their inhibitory activities against PKC and calmodulin‐dependent processes.