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CC BY-NC-ND 4.0 · Thromb Haemost 2022; 122(07): 1115-1129
DOI: 10.1055/a-1788-5322
Cellular Haemostasis and Platelets

Cucurbitacins Elicit Anti-Platelet Activity via Perturbation of the Cytoskeleton and Integrin Function

Neline Kriek
1   Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, University of Reading, Reading, United Kingdom
,
Sophie H. Nock
2   Department of Life Sciences, Faculty of Science and Engineering, Manchester Metropolitan University, Manchester, United Kingdom
,
Tanya Sage
1   Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, University of Reading, Reading, United Kingdom
,
Badrija Khalifa
2   Department of Life Sciences, Faculty of Science and Engineering, Manchester Metropolitan University, Manchester, United Kingdom
,
Alexander P. Bye
1   Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, University of Reading, Reading, United Kingdom
,
Joanne L. Mitchell
1   Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, University of Reading, Reading, United Kingdom
,
Steven Thomson
2   Department of Life Sciences, Faculty of Science and Engineering, Manchester Metropolitan University, Manchester, United Kingdom
,
Mark G. McLaughlin
3   Department of Chemistry, Lancaster University, Lancaster, United Kingdom
,
Sarah Jones
2   Department of Life Sciences, Faculty of Science and Engineering, Manchester Metropolitan University, Manchester, United Kingdom
,
Jonathan M. Gibbins
1   Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, University of Reading, Reading, United Kingdom
,
Amanda J. Unsworth 
1   Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, University of Reading, Reading, United Kingdom
2   Department of Life Sciences, Faculty of Science and Engineering, Manchester Metropolitan University, Manchester, United Kingdom
› Author Affiliations Funding This work was supported by a British Heart Foundation Project Grant PG/2019/34798 (to A.J.U.) and British Heart Foundation programme grants RG/15/2/31224 and RG/20/7/34866 (to J.M.G.), and research funds from the Centre for Bioscience at Manchester Metropolitan University and a Manchester Metropolitan University Internal Research Accelerator Grant: 343846 (to A.J.U.).
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Abstract

Cucurbitacins are dietary compounds that have been shown to elicit a range of anti-tumour, anti-inflammatory and anti-atherosclerotic activities. Originally identified as signal transducer and activator of transcription, STAT, inhibitors, a variety of mechanisms of action have since been described, including dysregulation of the actin cytoskeleton and disruption of integrin function. Integrin outside-in signalling and cytoskeletal rearrangements are critical for the propagation of stable thrombus formation and clot retraction following platelet adhesion at the site of vessel damage. The effects of cucurbitacins on platelet function and thrombus formation are unknown. We report for the first time anti-platelet and anti-thrombotic effects of cucurbitacins B, E and I in human platelets. Treatment of platelets with cucurbitacins resulted in attenuation of platelet aggregation, secretion and fibrinogen binding following stimulation by platelet agonists. Cucurbitacins were also found to potently inhibit other integrin- and cytoskeleton-mediated events, including adhesion, spreading and clot retraction. Further investigation of cytoskeletal dynamics found treatment with cucurbitacins altered cofilin phosphorylation, enhanced activation and increased F actin polymerisation and microtubule assembly. Disruption to cytoskeletal dynamics has been previously shown to impair integrin activation, platelet spreading and clot retraction. Anti-platelet properties of cucurbitacins were found to extend to a disruption of stable thrombus formation, with an increase in thrombi instability and de-aggregation under flow. Our research identifies novel, anti-platelet and anti-thrombotic actions of cucurbitacins that appear to be linked to dysregulation of cytoskeletal dynamics and integrin function.

Keywords

thrombosis - platelet - cytoskeleton - cucurbitacins - signalling

Author Contributions

Contribution: N.K., S.N., T.S., B.K., A.P.B., J.L.M., S.T., performed experiments and analysed results. M.G.M., S.J. and J.M.G. designed the research and wrote the paper. A.J.U. designed the research, performed experiments, analysed results and wrote the paper.


Supplementary Material



Publication History

Received: 18 May 2021

Accepted: 06 November 2021

Accepted Manuscript online:
04 March 2022

Article published online:
30 July 2022

© 2022. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

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