title: Calmodulin antagonists induce platelet apoptosis.
abstract: Calmodulin (CaM) antagonists induce apoptosis in various tumor models and inhibit tumor cell invasion and metastasis, thus some of which have been extensively used as anti-cancer agents. In platelets, CaM has 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. CaM antagonists did not incur platelet activation as detected by P-selectin surface expression and PAC-1 binding. However, ADP-, botrocetin-, and alpha-thrombin-induced platelet aggregation, platelet adhesion and spreading on von Willebrand factor surface were significantly reduced in platelets pre-treated with CaM antagonists. Furthermore, cytosolic Ca(2+) levels were obviously elevated by both W7 and TMX, and membrane-permeable Ca(2+) chelator BAPTA-AM significantly reduced apoptotic events in platelets induced by W7. Therefore, these findings indicate that CaM antagonists induce platelet apoptosis. The elevation of the cytosolic Ca(2+) levels may be involved in the regulation of CaM antagonists-induced platelet apoptosis.
authors.affiliation: School of Biological Science and Medical Engineering, Beihang University, Beijing, China.
authors.forename: Zhicheng
authors.initials: Z
authors.lastname: Wang
authors.forename: Suping
authors.initials: S
authors.lastname: Li
authors.forename: Quanwei
authors.initials: Q
authors.lastname: Shi
authors.forename: Rong
authors.initials: R
authors.lastname: Yan
authors.forename: Guanglei
authors.initials: G
authors.lastname: Liu
authors.forename: Kesheng
authors.initials: K
authors.lastname: Dai
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001792:Blood Platelets / Q000166:cytology / Q000378:metabolism*; D002147:Calmodulin / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism*; D061945:Caspase Inhibitors; D004533:Egtazic Acid / Q000031:analogs & derivatives; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000378:metabolism; D019007:P-Selectin / Q000378:metabolism / Q000494:pharmacology; D010718:Phosphatidylserines / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D015539:Platelet Activation / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000378:metabolism / Q000494:pharmacology; D013629:Tamoxifen / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D014268:Trifluoperazine / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D014841:von Willebrand Factor / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology
chemical_list: D002147:Calmodulin; D002352:Carrier Proteins; D061945:Caspase Inhibitors; D019007:P-Selectin; D010718:Phosphatidylserines; D010975:Platelet Aggregation Inhibitors; D014841:von Willebrand Factor; D013629:Tamoxifen; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D014268:Trifluoperazine; D004533:Egtazic Acid; D013917:Thrombin; D053148:Caspase 3