Estradiol derivatives bearing the side-chain of tamoxifen antagonize the association between the estrogen receptor and calmodulin.
Calmodulin (CaM) is known to associate with the estrogen receptor (ER). The antiestrogen tamoxifen impedes this association suggesting that the latter would play an important role in CaM-dependent enzymatic catalyses. The ethoxyaminoalkyl side-chain of tamoxifen which confers antiestrogenicity appears to be involved in this antagonism. Antiestrogenic estradiol derivatives bearing the side-chain of tamoxifen in position 11 beta (RU 39,411) or 7 alpha (RU 45,144) were tested for their potential antagonism towards the association between CaM and ER. According to molecular modelling studies, such graftings position the chain in an orientation corresponding to that found in tamoxifen. Both compounds impeded the binding of ER to CaM-Sepharose at the same concentrations as found with tamoxifen indicating similar effectiveness. Steroidal analogs with or without a side-chain in a non-appropriate orientation failed to show this property. On the contrary, a non-conjugated side-chain analog antagonized the binding of the receptor indicating that the steroidal backbone of RU 39,411 and RU 45,144 did not play a major role in this regard. Since this free side-chain had been reported to be totally devoid of antiestrogenicity, one may consider that the steroidal backbone of these two antiestrogens participate to their antiproliferative activity. One may speculate that within the cell, ER should convey such compounds to CaM leading to a blockade of CaM-dependent catalyses. This hypothesis would also be relevant to the stilbene backbone of tamoxifen.
Bouhoute
A
A
Laboratoire J.C. Heuson de Cancérologie Mammaire, Institut Jules Bordet, Bruxelles, Belgium.
Leclercq
G
G
D000818:Animals; D002147:Calmodulin / Q000378:metabolism*; D004958:Estradiol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology*; D005260:Female; D051381:Rats; D011960:Receptors, Estrogen / Q000187:drug effects / Q000378:metabolism*; D013629:Tamoxifen / Q000737:chemistry* / Q000494:pharmacology
D002147:Calmodulin; D004965:Estrogen Antagonists; D011960:Receptors, Estrogen; D013629:Tamoxifen; C086199:RU 45144; C060411:RU 39411; D004958:Estradiol