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The Marine-Derived Triterpenoid Frondoside A Inhibits Thrombus Formation

Institute for Clinical & Experimental Surgery, Saarland University, 66421 Homburg/Saar, Germany
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Mar. Drugs 2020, 18(2), 111; https://doi.org/10.3390/md18020111
Received: 22 November 2019 / Revised: 10 February 2020 / Accepted: 11 February 2020 / Published: 14 February 2020
(This article belongs to the Special Issue Marine Molecules for the Treatment of Thrombosis)
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. View Full-Text
Keywords: frondoside A; thrombus formation; thrombosis; hemostasis; platelets; PI3K; dorsal skinfold chamber frondoside A; thrombus formation; thrombosis; hemostasis; platelets; PI3K; dorsal skinfold chamber
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Ampofo, E.; Später, T.; Nalbach, L.; Menger, M.D.; Laschke, M.W. The Marine-Derived Triterpenoid Frondoside A Inhibits Thrombus Formation. Mar. Drugs 2020, 18, 111.

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