Tamoxifen stimulates calcium entry into human platelets.
The anti-estrogenic drug tamoxifen, which is used therapeutically for treatment and prevention of breast cancer, can lead to the development of thrombosis. We found that tamoxifen rapidly increased intracellular free calcium [Ca2+]i in human platelets from both male and female donors. Thus 10 microM tamoxifen increased [Ca2+]i above the resting level by 197 +/- 19%. Tamoxifen acted synergistically with thrombin, ADP, and vasopressin to increase [Ca2+]i. The anti-estrogen ICI 182780 did not attenuate the effects of tamoxifen to increase [Ca2+]i; however, phospholipase C inhibitor U-73122 blocked this effect. 4-hydroxytamoxifen, a major metabolite of tamoxifen, also increased [Ca2+]i, but other tamoxifen metabolites and synthetic derivatives did not. Three hydroxylated derivatives of triphenylethylene (corresponding to the hydrophobic core of tamoxifen) which are transitional structures between tamoxifen (Ca agonist) and diethylstilbestrol (Ca antagonist) increased [Ca2+]i slightly (6% to 24%) and partially inhibited thrombin-induced [Ca2+]i elevation (68% to 79%). Therefore the dimethylaminoethyl moiety is responsible for tamoxifen being a Ca agonist rather than antagonist. 4-Hydroxytamoxifen and polymer-conjugated derivatives of 4-hydroxytamoxifen increased [Ca2+]i, with similar efficacy. The ability of tamoxifen to increase [Ca2+]i in platelets, leading to platelet activation, and its ability to act synergistically with other platelet agonists may contribute to development of tamoxifen-induced thrombosis.
Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk, VA 23501-1980, USA.
Yuliya
Y
Dobrydneva
Ross V
RV
Weatherman
Joseph P
JP
Trebley
Melinda M
MM
Morrell
Megan C
MC
Fitzgerald
Craig E
CE
Fichandler
Nithiananda
N
Chatterjie
Peter F
PF
Blackmore
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000328:Adult; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D004054:Diethylstilbestrol / Q000494:pharmacology; D004357:Drug Synergism; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D004963:Estrenes / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D004978:Ethamoxytriphetol / Q000494:pharmacology; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D008297:Male; D008875:Middle Aged; D015394:Molecular Structure; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D013267:Stilbenes / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D013917:Thrombin / Q000494:pharmacology; D014667:Vasopressins / Q000494:pharmacology
D004963:Estrenes; D004965:Estrogen Antagonists; D010726:Phosphodiesterase Inhibitors; D011760:Pyrrolidinones; D013267:Stilbenes; C454061:ethylbromide tamoxifen; D013629:Tamoxifen; D014667:Vasopressins; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; C016601:afimoxifene; D000077267:Fulvestrant; D004958:Estradiol; D000244:Adenosine Diphosphate; D004978:Ethamoxytriphetol; D004054:Diethylstilbestrol; C035830:tamoxifen N-oxide; C049433:desdimethyltamoxifen; D013917:Thrombin; C037749:triphenylethylene; D002118:Calcium