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Published on: May 24, 2024
The Marine-Derived Kinase Inhibitor Fascaplysin Exerts Anti-Thrombotic Activity
Emmanuel Ampofo1, Thomas Später2, Isabelle Müller3
1Institute for Clinical and Experimental Surgery, Saarland University, 66421 Homburg/Saar, Germany. emmanuel.ampofo@uks.eu.
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.
Insights
The marine compound fascaplysin inhibits platelet activation and aggregation, reducing thrombus formation and bleeding time in mice. This demonstrates its novel anti-thrombotic properties.
Area of Science:
- Pharmacology
- Hematology
- Marine Biotechnology
Background:
- Fascaplysin, a marine-derived kinase inhibitor, targets the PI3K pathway implicated in cancer.
- The PI3K pathway is crucial for platelet signaling and thrombosis.
- This study investigates fascaplysin's impact on thrombosis due to its known pathway interactions.
Purpose of the Study:
- To evaluate the anti-thrombotic effects of fascaplysin.
- To determine fascaplysin's influence on platelet activation, aggregation, and thrombus formation in vivo.
- To explore a novel application of fascaplysin beyond its known kinase inhibitory activities.
Main Methods:
- Flow cytometry was used to analyze platelet activation, aggregation, and platelet-leukocyte aggregate (PLA) formation.
- In vivo thrombosis was assessed using a mouse dorsal skinfold chamber model with photochemical induction.
- Tail-vein bleeding time was measured to evaluate hemostatic effects.
Main Results:
- Fascaplysin reduced glycoprotein (GP)IIb/IIIa activation and platelet aggregation in response to various agonists.
- Fascaplysin decreased PLA formation with PMA stimulation but not with PAR-1-AP or ADP.
- In vivo, fascaplysin significantly prolonged vessel occlusion time and increased bleeding time in mice.
Conclusions:
- Fascaplysin exhibits significant anti-thrombotic activity.
- This anti-thrombotic effect represents a new facet of fascaplysin's diverse biological actions.
- Fascaplysin shows potential as a therapeutic agent for thrombotic disorders.
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