Antagonism of estrogen receptor and calmodulin association by antiestrogens is not dependent on an interaction with calmodulin.
Previously, two antiestrogens estradiol derivatives (3 and 4) bearing the basic side chain of tamoxifen were shown to impede the binding of the estrogen receptor (ER) to calmodulin (CaM)-Sepharose. In this study, the interaction of these and related compounds with calmodulin was examined using the cyclic AMP phosphodiesterase (cAMP-PDE) assay. Neither of the steroids gave any significant inhibition of the calmodulin dependent cAMP-PDE activity up to a final concentration of 20 microM. For comparison, tamoxifen and nafoxidine produced IC50 values of 6.7 microM +/- 1.0 and 7.4 microM +/- 1.1, respectively. In addition, a comparison was made of the activity of some triphenylethylene derivatives against CaM dependent cAMP-PDE and the ER-CaM Sepharose assays, but no relationship was observed. Overall, these results demonstrate that inhibition of the ER-CaM association by various steroidal and triphenylethylene antiestrogens does not relate to antagonism of calmodulin function or their binding affinity for the estrogen receptor.
Rowlands
M G
MG
Cancer Research Campaign Centre for Cancer Therapeutics, Institute of Cancer Research, CRC Laboratory, Belmont, Sutton, Surrey, U.K.
Grimshaw
R
R
Jarman
M
M
Bouhoute
A
A
Leclercq
G
G
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D002147:Calmodulin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D004965:Estrogen Antagonists / Q000494:pharmacology*; D011960:Receptors, Estrogen / Q000378:metabolism*; D013329:Structure-Activity Relationship
D002147:Calmodulin; D004965:Estrogen Antagonists; D011960:Receptors, Estrogen; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1