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Molecular mechanism of tamoxifen‐induced calcium influx in human platelets
Author(s) -
Dobrydneva Yuliya,
Weatherman Ross,
Blackmore Peter
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a1349-d
Subject(s) - tamoxifen , pharmacology , chemistry , calcium , endocrinology , wortmannin , medicine , apocynin , estrogen receptor , nadph oxidase , biology , kinase , biochemistry , phosphatidylinositol , cancer , oxidative stress , breast cancer
Tamoxifen, a non steroidal estrogen antagonist, is the most widely used drug for treatment and prevention of breast cancer. However, tamoxifen can cause thrombosis by an unknown mechanism. Using fura‐2 to measure intracellular calcium in freshly isolated human platelets, we found that tamoxifen and its major metabolite 4‐hydroxy tamoxifen at 5–10 uM promote calcium influx into platelets. Tamoxifen also potentiates action of platelet agonists (thrombin, vasopressin, ADP) to raise calcium. Tamoxifen effect was not attenuated by estrogen receptor antagonist ICI 182780 or COX inhibitor aspirin, but was blocked by the PLC inhibitor U‐73122. Tamoxifen‐induced calcium elevation was blocked by the lipid‐soluble antioxidant vitamin E, but was unaffected by water‐soluble vitamin C and quercetin. Tamoxifen effect was also blocked by the NADPH inhibitor apocynin and by wortmannin, an inhibitor of PI3 kinase, an upstream effector of NADPH oxidase. High molecular weight derivatives of 4‐hydroxy tamoxifen conjugated to poly‐methacrylic acid also promoted calcium elevation in platelets. An anti‐estrogenic drug raloxifene, which is structurally related to tamoxifen, does not affect platelet calcium entry. Therefore tamoxifen may affect membrane‐bound PLC, NADPH oxidase and PI3 kinase, leading to the activation of store‐operated calcium channels, calcium entry into platelets, platelet activation and aggregation, which may be an underlying mechanism of tamoxifen‐induced thrombosis. (Supported by grants from CHRB of Virginia and Cancer Research and Prevention Foundation to YD and Army Breast Cancer Research Program to RW).