A novel role for tamoxifen in the inhibition of human platelets

Tamoxifen, a selective estrogen receptor (ER) modulator (SERM), is widely used therapeutically for the treatment and prevention of breast cancer, but its use is associated with an increased risk of thrombosis. The mechanism of this adverse effect is still unclear. Arterial thromboses mostly consist of platelets that are adherent to ruptured endothelial surfaces. Several lines of evidence reported that tamoxifen stimulates platelet activation using different methodologies. In our preliminary study, tamoxifen exhibited potent antiplatelet activity in washed human platelets. The aim of this study was to examine the signal transduction pathways of tamoxifen in platelet activation. In this study, tamoxifen (3∼7 μmol/L) exhibited more potent activity in inhibiting platelet aggregation stimulated by collagen than other agonists (ie, thrombin). Tamoxifen inhibited collagen-stimulated platelet activation accompanied by relative Ca⁺² mobilization, thromboxane A₂ (TxA ₂) formation, and phospholipase C (PLC)γ2, protein kinase C (PKC), and mitogen-activated protein kinase (MAPK) phosphorylation (ie, p38 MAPK and extracellular signal-regulated kinase 1/2), but not hydroxyl radical (OH^•) formation. However, tamoxifen did not increase nitric oxide (NO) release or vasodilator-stimulated phosphoprotein (VASP) phosphorylation in washed platelets. Furthermore, neither ICI 182,780, a pure ER antagonist, nor ODQ, an inhibitor of guanylate cyclase, significantly reversed the tamoxifen-mediated inhibition of platelet aggregation. In conclusion, this study demonstrates for the first time that tamoxifen possesses potent antiplatelet activity, the mechanism of which may be involved in the inhibition of the PLCγ2-PKC-p38 MAPK-TxA₂ cascade, thereby leading to the inhibition of platelet activation. In our study, the direct inhibition of platelet activation by tamoxifen possibly may provide new insights into understanding its cardiovascular effects.