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Critical off‐target effects of the widely used Rac1 inhibitors NSC23766 and EHT1864 in mouse platelets

Dütting, S., Heidenreich, J., Cherpokova, D., Amin, E., Zhang, S.‐C., Ahmadian, M.R., Brakebusch, C., Nieswandt, B.·2015·Journal of Thrombosis and Haemostasis
DOI 10.1111/jth.12861
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Abstract

Background Platelet aggregation at sites of vascular injury is essential for normal hemostasis, but may also cause pathologic vessel occlusion. Rho GTPases are molecular switches that regulate essential cellular processes, and they have pivotal functions in the cardiovascular system. Rac1 is an important regulator of platelet cytoskeletal reorganization, and contributes to platelet activation. Rac1 inhibitors are thought to be beneficial in a wide range of therapeutic settings, and have therefore been tested in vivo for a variety of disorders. Two small-molecule inhibitors, NSC23766 and EHT1864, have been characterized in different cell types, demonstrating high specificity for Rac1 and Rac, respectively. Objectives To analyze the specificity of NSC23766 and EHT1864. Methods Platelet function was assessed in mouse wild-type and Rac1-deficient platelets by the use of flow cytometric analysis of cellular activation and aggregometry. Platelet spreading was analyzed with differential interference contrast microscopy, and activation of effector molecules was analyzed with biochemical approaches. Results NSC23766 and EHT1864 showed strong and distinct Rac1-independent effects at 100 μm in platelet function tests. Both inhibitors induced Rac1-specific inhibition of platelet spreading, but also markedly impaired agonist-induced activation of Rac1(-/-) platelets. Furthermore, glycoprotein Ib-mediated signaling was dramatically inhibited by NSC23766 in both wild-type and Rac1-deficient…

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Metadata

Authors
Dütting, S., Heidenreich, J., Cherpokova, D., Amin, E., Zhang, S. ‐., Ahmadian, M. R., Brakebusch, C., & Nieswandt, B.
Venue
Journal of Thrombosis and Haemostasis
Publisher
Elsevier BV
Published
2015-05
Volume
13
Issue
5
Pages
827-838
ISSN
1538-7836
DOI
10.1111/jth.12861
Cited by
81
References
2
Language
en
Licence
Funders
  • Deutsche Forschungsgemeinschaft (Ni556/9-1)
  • Nieswandt and Sonderforschungsbereich [SFB] (688)
  • International Research Training Group [IRTG] (1902)

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