title: The Marine-Derived Kinase Inhibitor Fascaplysin Exerts Anti-Thrombotic Activity.
abstract: BACKGROUND
  The marine-derived kinase inhibitor fascaplysin down-regulates the PI3K pathway in cancer cells. Since this pathway also plays an essential role in platelet signaling, we herein investigated the effect of fascaplysin on thrombosis.
  
  
  METHODS
  Fascaplysin effects on platelet activation, platelet aggregation and platelet-leukocyte aggregates (PLA) formation were analyzed by flow cytometry. Mouse dorsal skinfold chambers were used to determine in vivo the effect of fascaplysin on photochemically induced thrombus formation and tail-vein bleeding time.
  
  
  RESULTS
  Pre-treatment of platelets with fascaplysin reduced the activation of glycoprotein (GP)IIb/IIIa after protease-activated receptor-1-activating peptide (PAR-1-AP), adenosine diphosphate (ADP) and phorbol-12-myristate-13-acetate (PMA) stimulation, but did not markedly affect the expression of P-selectin. This was associated with a decreased platelet aggregation. Fascaplysin also decreased PLA formation after PMA but not PAR-1-AP and ADP stimulation. This may be explained by an increased expression of CD11b on leukocytes in PAR-1-AP- and ADP-treated whole blood. In the dorsal skinfold chamber model of photochemically induced thrombus formation, fascaplysin-treated mice revealed a significantly extended complete vessel occlusion time when compared to controls. Furthermore, fascaplysin increased the tail-vein bleeding time.
  
  
  CONCLUSIONS
  Fascaplysin exerts anti-thrombotic activity, which represents a novel mode of action in the pleiotropic activity spectrum of this compound.
authors.affiliation: Institute for Clinical and Experimental Surgery, Saarland University, 66421 Homburg/Saar, Germany. emmanuel.ampofo@uks.eu.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Ampofo
authors.affiliation: Institute for Clinical and Experimental Surgery, Saarland University, 66421 Homburg/Saar, Germany. tomcali@icloud.com.
authors.forename: Thomas
authors.initials: T
authors.lastname: Später
authors.affiliation: Institute for Hemostasiology and Transfusion Medicine, Saarland University, 66421 Homburg/Saar, Germany. isabelle.muller@uks.eu.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Müller
authors.affiliation: Institute for Hemostasiology and Transfusion Medicine, Saarland University, 66421 Homburg/Saar, Germany. hermann.eichler@uks.eu.
authors.forename: Hermann
authors.initials: H
authors.lastname: Eichler
authors.affiliation: Institute for Clinical and Experimental Surgery, Saarland University, 66421 Homburg/Saar, Germany. michael.menger@uks.eu.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Menger
authors.affiliation: Institute for Clinical and Experimental Surgery, Saarland University, 66421 Homburg/Saar, Germany. matthias.laschke@uks.eu.
authors.forename: Matthias W
authors.initials: MW
authors.lastname: Laschke
mesh_terms: D000244:Adenosine Diphosphate / Q000008:administration & dosage; D000818:Animals; D004195:Disease Models, Animal; D005434:Flow Cytometry; D007211:Indoles / Q000494:pharmacology*; D007962:Leukocytes / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009842:Oligopeptides / Q000008:administration & dosage; D015539:Platelet Activation / Q000187:drug effects*; D010974:Platelet Aggregation / Q000187:drug effects*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000008:administration & dosage; D013927:Thrombosis / Q000188:drug therapy* / Q000473:pathology; D000644:Quaternary Ammonium Compounds; D002243:Carbolines; D007212:Indolizines
chemical_list: D000244:Adenosine Diphosphate; D007211:Indoles; D009842:Oligopeptides; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D013755:Tetradecanoylphorbol Acetate; C462999:PAR-1-activating peptide; C069346:fascaplysine; D000644:Quaternary Ammonium Compounds; D002243:Carbolines; D007212:Indolizines
keywords: CD11b; GPIIb/IIIa; P-selectin; dorsal skinfold chamber; fascaplysin; leukocytes; platelets; thrombosis