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Calmodulin antagonists induce platelet apoptosis
Thrombosis Research 125 (2010) 340-350,-0001,():
Calmodulin (CaM) antagonists induce apoptosis in various tumor models and inhibit tumor cell invasion and metastasis, thus some ofwhich have been extensively used as anti-cancer agents. In platelets, CaMhas been found to bind directly to the cytoplasmic domains of several platelet receptors. Incubation of platelets with CaM antagonists impairs the receptors-related platelet functions. However, it is still unknown whether CaM antagonists induce platelet apoptosis. Here we show that CaM antagonists N-(6-aminohexyl)-5-chloro-1-naphthalene sulfonamide (W7), tamoxifen (TMX), and trifluoperazine (TFP) induce apoptotic events in human platelets, including depolarization of mitochondrial inner transmembrane potential, caspase-3 activation, and phosphatidylserine exposure. CaMantagonists did not incur platelet activation as detected by P-selectin surface expression and PAC-1 binding. However, ADP-, botrocetin-, and α-thrombin-induced platelet aggregation, platelet adhesion and spreading on von Willebrand factor surface were significantly reduced in platelets pretreatedwith CaM antagonists. Furthermore, cytosolic Ca2+ levelswere obviously elevated by both W7and TMX, and membrane-permeable Ca2+ chelator BAPTA AMsignificantly reduced apoptotic events in platelets induced by W7. Therefore, these findings indicate that CaM antagonists induce platelet apoptosis. The elevation of the cytosolic Ca2+ levels may be involved in the regulation of CaM antagonists-induced platelet apoptosis.
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