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The Marine-Derived Kinase Inhibitor Fascaplysin Exerts Anti-Thrombotic Activity.

Ampofo E, Später T, Müller I, Eichler H, Menger MD, Laschke MW - Mar Drugs (2015)

Bottom Line: This was associated with a decreased platelet aggregation.Fascaplysin also decreased PLA formation after PMA but not PAR-1-AP and ADP stimulation.Fascaplysin exerts anti-thrombotic activity, which represents a novel mode of action in the pleiotropic activity spectrum of this compound.

View Article: PubMed Central - PubMed

Affiliation: Institute for Clinical and Experimental Surgery, Saarland University, 66421 Homburg/Saar, Germany. emmanuel.ampofo@uks.eu.

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.

Conclusion: Fascaplysin exerts anti-thrombotic activity, which represents a novel mode of action in the pleiotropic activity spectrum of this compound.

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Related in: MedlinePlus

Effect of fascaplysin on platelet aggregation. (A–C) Typical diagrams of aggregation results for WP, which were incubated with 10 μM fascaplysin (black lines) or vehicle (grey lines) for 0.5 h prior to the stimulation with PAR-1-AP (A); ADP (B); or PMA (C).
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marinedrugs-13-06774-f003: Effect of fascaplysin on platelet aggregation. (A–C) Typical diagrams of aggregation results for WP, which were incubated with 10 μM fascaplysin (black lines) or vehicle (grey lines) for 0.5 h prior to the stimulation with PAR-1-AP (A); ADP (B); or PMA (C).

Mentions: Based on our finding that fascaplysin suppresses the activation of GPIIb/IIIa, we next analyzed the aggregation capacity of fascaplysin-treated washed platelets. As expected, treatment of washed platelets with 10 μM fascaplysin resulted in an attenuated agonist-induced platelet aggregation (Figure 3A–C).


The Marine-Derived Kinase Inhibitor Fascaplysin Exerts Anti-Thrombotic Activity.

Ampofo E, Später T, Müller I, Eichler H, Menger MD, Laschke MW - Mar Drugs (2015)

Effect of fascaplysin on platelet aggregation. (A–C) Typical diagrams of aggregation results for WP, which were incubated with 10 μM fascaplysin (black lines) or vehicle (grey lines) for 0.5 h prior to the stimulation with PAR-1-AP (A); ADP (B); or PMA (C).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4663553&req=5

marinedrugs-13-06774-f003: Effect of fascaplysin on platelet aggregation. (A–C) Typical diagrams of aggregation results for WP, which were incubated with 10 μM fascaplysin (black lines) or vehicle (grey lines) for 0.5 h prior to the stimulation with PAR-1-AP (A); ADP (B); or PMA (C).
Mentions: Based on our finding that fascaplysin suppresses the activation of GPIIb/IIIa, we next analyzed the aggregation capacity of fascaplysin-treated washed platelets. As expected, treatment of washed platelets with 10 μM fascaplysin resulted in an attenuated agonist-induced platelet aggregation (Figure 3A–C).

Bottom Line: This was associated with a decreased platelet aggregation.Fascaplysin also decreased PLA formation after PMA but not PAR-1-AP and ADP stimulation.Fascaplysin exerts anti-thrombotic activity, which represents a novel mode of action in the pleiotropic activity spectrum of this compound.

View Article: PubMed Central - PubMed

Affiliation: Institute for Clinical and Experimental Surgery, Saarland University, 66421 Homburg/Saar, Germany. emmanuel.ampofo@uks.eu.

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.

Conclusion: Fascaplysin exerts anti-thrombotic activity, which represents a novel mode of action in the pleiotropic activity spectrum of this compound.

Show MeSH
Related in: MedlinePlus