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ML355 Modulates Platelet Activation and Prevents ABT-737 Induced Apoptosis in Platelets
12-lipoxigenase (12-LOX) is implicated in regulation of platelet activation processes and can be a new promising target for antiplatelet therapy. However, investigations of 12-LOX were restricted by the lack of specific and potent 12-LOX inhibitors and by controversial data concerning the role of 12...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Biochemistry and Molecular Biology
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9073945/ https://www.ncbi.nlm.nih.gov/pubmed/35197320 http://dx.doi.org/10.1124/jpet.121.000973 |
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author | Shpakova, Valentina Rukoyatkina, Natalia Al Arawe, Nada Prilepskaya, Anna Kharazova, Alexandra Sharina, Iraida Gambaryan, Stepan Martin, Emil |
author_facet | Shpakova, Valentina Rukoyatkina, Natalia Al Arawe, Nada Prilepskaya, Anna Kharazova, Alexandra Sharina, Iraida Gambaryan, Stepan Martin, Emil |
author_sort | Shpakova, Valentina |
collection | PubMed |
description | 12-lipoxigenase (12-LOX) is implicated in regulation of platelet activation processes and can be a new promising target for antiplatelet therapy. However, investigations of 12-LOX were restricted by the lack of specific and potent 12-LOX inhibitors and by controversial data concerning the role of 12-LOX metabolites in platelet functions. A novel specific 12-LOX inhibitor ML355 was shown to inhibit platelet aggregation without adverse side effects on hemostasis; however, the molecular mechanisms of its action on platelets are poorly understood. Here, we showed that ML355 inhibited platelet activation induced by thrombin or thromboxane A(2), but not by collagen-related peptide. ML355 blocked protein kinase B, phosphoinositide 3-kinase, and extracellular signal-regulated kinase, but not p38 kinase, spleen tyrosine kinase (Syk), or phospholipase Cγ2 phosphorylation in activated platelets. The main inhibitory effect of low doses of ML355 (1–20 μM) on thrombin activated platelets was mediated by the decrease in reactive oxygen species level, whereas high doses of ML355 (50 μM) caused cyclic adenosine monophosphate activation. ML355 did not affect the activity of nitric oxide-dependent soluble guanylyl cyclase, nor did it affect the relaxation of preconstricted aortic rings in mice. ML355 itself did not affect platelet viability, but at 50 μM dose blocked caspase-dependent apoptosis induced by B-cell lymphoma II inhibitor ABT-737. SIGNIFICANCE STATEMENT: The current paper provides novel and original data concerning molecular mechanisms of 12-LOX inhibitor ML355 action on platelets. These data reveal antiplatelet and protective effects of ML355 on platelets and may be of importance for both antiplatelet and anticancer therapy. |
format | Online Article Text |
id | pubmed-9073945 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Society for Biochemistry and Molecular Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-90739452022-05-06 ML355 Modulates Platelet Activation and Prevents ABT-737 Induced Apoptosis in Platelets Shpakova, Valentina Rukoyatkina, Natalia Al Arawe, Nada Prilepskaya, Anna Kharazova, Alexandra Sharina, Iraida Gambaryan, Stepan Martin, Emil J Pharmacol Exp Ther Cellular and Molecular 12-lipoxigenase (12-LOX) is implicated in regulation of platelet activation processes and can be a new promising target for antiplatelet therapy. However, investigations of 12-LOX were restricted by the lack of specific and potent 12-LOX inhibitors and by controversial data concerning the role of 12-LOX metabolites in platelet functions. A novel specific 12-LOX inhibitor ML355 was shown to inhibit platelet aggregation without adverse side effects on hemostasis; however, the molecular mechanisms of its action on platelets are poorly understood. Here, we showed that ML355 inhibited platelet activation induced by thrombin or thromboxane A(2), but not by collagen-related peptide. ML355 blocked protein kinase B, phosphoinositide 3-kinase, and extracellular signal-regulated kinase, but not p38 kinase, spleen tyrosine kinase (Syk), or phospholipase Cγ2 phosphorylation in activated platelets. The main inhibitory effect of low doses of ML355 (1–20 μM) on thrombin activated platelets was mediated by the decrease in reactive oxygen species level, whereas high doses of ML355 (50 μM) caused cyclic adenosine monophosphate activation. ML355 did not affect the activity of nitric oxide-dependent soluble guanylyl cyclase, nor did it affect the relaxation of preconstricted aortic rings in mice. ML355 itself did not affect platelet viability, but at 50 μM dose blocked caspase-dependent apoptosis induced by B-cell lymphoma II inhibitor ABT-737. SIGNIFICANCE STATEMENT: The current paper provides novel and original data concerning molecular mechanisms of 12-LOX inhibitor ML355 action on platelets. These data reveal antiplatelet and protective effects of ML355 on platelets and may be of importance for both antiplatelet and anticancer therapy. American Society for Biochemistry and Molecular Biology 2022-05 2022-05 /pmc/articles/PMC9073945/ /pubmed/35197320 http://dx.doi.org/10.1124/jpet.121.000973 Text en Copyright © 2022 by The Author(s) https://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed under the CC BY-NC Attribution 4.0 International license (https://creativecommons.org/licenses/by-nc/4.0/) . |
spellingShingle | Cellular and Molecular Shpakova, Valentina Rukoyatkina, Natalia Al Arawe, Nada Prilepskaya, Anna Kharazova, Alexandra Sharina, Iraida Gambaryan, Stepan Martin, Emil ML355 Modulates Platelet Activation and Prevents ABT-737 Induced Apoptosis in Platelets |
title | ML355 Modulates Platelet Activation and Prevents ABT-737 Induced Apoptosis in Platelets |
title_full | ML355 Modulates Platelet Activation and Prevents ABT-737 Induced Apoptosis in Platelets |
title_fullStr | ML355 Modulates Platelet Activation and Prevents ABT-737 Induced Apoptosis in Platelets |
title_full_unstemmed | ML355 Modulates Platelet Activation and Prevents ABT-737 Induced Apoptosis in Platelets |
title_short | ML355 Modulates Platelet Activation and Prevents ABT-737 Induced Apoptosis in Platelets |
title_sort | ml355 modulates platelet activation and prevents abt-737 induced apoptosis in platelets |
topic | Cellular and Molecular |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9073945/ https://www.ncbi.nlm.nih.gov/pubmed/35197320 http://dx.doi.org/10.1124/jpet.121.000973 |
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