Abstract
Background: The marine-derived triterpenoid frondoside A inhibits the phosphatidylinositol-3-kinase (PI3K) pathway in cancer cells. Because this pathway is also crucially involved in platelet activation, we studied the effect of frondoside A on thrombus formation. Methods: Frondoside A effects on platelet viability, surface adhesion molecule expression, and intracellular signaling were analyzed by flow cytometry and Western blot. The effect of frondoside A was analyzed by photochemically induced thrombus formation in the mouse dorsal skinfold chamber model and by tail vein bleeding. Results: Concentrations of up to 15 µM frondoside A did not affect the viability of platelets, but reduced their surface expression of P-selectin (CD62P) and the activation of glycoprotein (GP)IIb/IIIa after agonist stimulation. Additional mechanistic analyses revealed that this was mediated by downregulation of PI3K-dependent Akt and extracellular-stimuli-responsive kinase (ERK) phosphorylation. Frondoside A significantly prolonged the complete vessel occlusion time in the mouse dorsal skinfold chamber model of photochemically induced thrombus formation and also the tail vein bleeding time when compared to vehicle-treated controls. Conclusion: Our findings demonstrated that frondoside A inhibits agonist-induced CD62P expression and activation of GPIIb/IIIa. Moreover, frondoside A suppresses thrombus formation. Therefore, this marine-derived triterpenoid may serve as a lead compound for the development of novel antithrombotic drugs.
Highlights
Thrombus formation is triggered by intravascular blood clotting as a result of hyperaggregability of platelets, increased blood viscosity, and impaired fibrinolysis
In a first set of experiments, we determined suitable concentrations of frondoside A to exclude the possibility that the analyzed effects of this compound may be due to platelet toxicity
We identified the triterpenoid frondoside A from the Atlantic sea cucumber Cucumaria frondosa as a novel antithrombotic compound which is capable of reducing agonist-induced platelet activation via the inhibition of this pathway
Summary
Thrombus formation is triggered by intravascular blood clotting as a result of hyperaggregability of platelets, increased blood viscosity, and impaired fibrinolysis. Antiplatelet drugs target specific surface proteins, including adenosine diphosphate (ADP) and glycoprotein (GP)IIb/IIIa receptors, as well as intracellular proteins, such as cyclooxygenase [2]. The marine-derived triterpenoid frondoside A inhibits the phosphatidylinositol-3-kinase (PI3K) pathway in cancer cells. Because this pathway is crucially involved in platelet activation, we studied the effect of frondoside A on thrombus formation. Results: Concentrations of up to 15 μM frondoside A did not affect the viability of platelets, but reduced their surface expression of P-selectin (CD62P) and the activation of glycoprotein (GP)IIb/IIIa after agonist stimulation. This marine-derived triterpenoid may serve as a lead compound for the development of novel antithrombotic drugs
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
