title: Inhibition of rat platelet aggregation by mycalolide-B, a novel inhibitor of actin polymerization with a different mechanism of action from cytochalasin-D.
abstract: In vitro effects of mycalolide-B (MB), isolated from marine sponge, were investigated with regard to the activation of rat platelets. Collagen-induced platelet aggregation in platelet-rich plasma (PRP) was slightly but significantly potentiated by lower concentrations of MB (0.3 and 1 microM) but was inhibited by higher concentrations (3 and 10 microM). ADP-induced platelet aggregation in PRP was also significantly prevented by MB (1-10 microM). Potentiation of ADP-induced aggregation by MB (0.3 microM) was hardly observed. G-actin contents, determined by DNase I inhibition assay, were increased in resting washed platelets incubated with MB (3 microM). In contrast, cytochalasin-D (CD) at 3 microM slightly reduced G-actin contents in resting platelets. After platelet aggregation with collagen (3 microg/ml) or ADP (10 microM), G-actin contents in platelets were reduced, indicating de novo actin polymerization. MB (3 microM) and CD (3 microM) abolished both ADP (10 microM)- and collagen (3 microg/ml)-induced platelet aggregation and actin polymerization in washed platelets. MB (1-10 microM) had no effects on intracellular Ca2+ concentrations in ADP (10 microM)-stimulated platelets. [125I]-fibrinogen binding to activated platelets with ADP (10 microM)(was inhibited by MB (0.3-3 microM) in a concentration-dependent manner. Thrombin-induced platelet-fibrin clot retraction was inhibited by MB (1 and 10 microM). These results suggest that MB inhibits platelet activation by interfering with actin polymerization through a different mechanism of action from CD. MB may be a useful tool for studying the role of actin polymerization in various cells.
authors.affiliation: Pharmacology and Molecular Biology Research Laboratories, Sankyo Co., Ltd., Tokyo, Japan. atsuhi@shina.sankyo.co.jp
authors.forename: A
authors.initials: A
authors.lastname: Sugidachi
authors.forename: T
authors.initials: T
authors.lastname: Ogawa
authors.forename: F
authors.initials: F
authors.lastname: Asai
authors.forename: S
authors.initials: S
authors.lastname: Saito
authors.forename: H
authors.initials: H
authors.lastname: Ozaki
authors.forename: N
authors.initials: N
authors.lastname: Fusetani
authors.forename: H
authors.initials: H
authors.lastname: Karaki
authors.forename: H
authors.initials: H
authors.lastname: Koike
mesh_terms: D000199:Actins / Q000187:drug effects; D000818:Animals; D001792:Blood Platelets / Q000473:pathology* / Q000502:physiology; D015638:Cytochalasin D / Q000494:pharmacology*; D019281:Dimerization; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008297:Male; D008387:Marine Toxins; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology*; D010080:Oxazoles / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000199:Actins; D004791:Enzyme Inhibitors; D008387:Marine Toxins; D019384:Nucleic Acid Synthesis Inhibitors; D010080:Oxazoles; D010975:Platelet Aggregation Inhibitors; C080978:mycalolide B; D015638:Cytochalasin D