(Homo-)harringtonine prevents endothelial inflammation through IRF-1 dependent downregulation of VCAM1 mRNA expression and inhibition of cell adhesion molecule protein biosynthesis.

Autor: Burgers LD; Institute of Pharmaceutical Biology, Faculty of Biochemistry, Chemistry and Pharmacy, Goethe University, Frankfurt am Main, Germany., Ciurus S; Institute of Pharmaceutical Biology, Faculty of Biochemistry, Chemistry and Pharmacy, Goethe University, Frankfurt am Main, Germany., Engel P; Institute of Pharmacology and Clinical Pharmacy, Faculty of Biochemistry, Chemistry and Pharmacy, Goethe University, Frankfurt am Main, Germany., Kuntschar S; Institute of Biochemistry I, Faculty of Medicine, Goethe University, Frankfurt am Main, Germany., Raue R; Institute of Biochemistry I, Faculty of Medicine, Goethe University, Frankfurt am Main, Germany., Kiprina A; Institute of Biochemistry I, Faculty of Medicine, Goethe University, Frankfurt am Main, Germany., Primke T; Institute of Pharmaceutical Biology, Faculty of Biochemistry, Chemistry and Pharmacy, Goethe University, Frankfurt am Main, Germany., Schmid T; Institute of Biochemistry I, Faculty of Medicine, Goethe University, Frankfurt am Main, Germany., Weigert A; Institute of Biochemistry I, Faculty of Medicine, Goethe University, Frankfurt am Main, Germany., Schmidtko A; Institute of Pharmacology and Clinical Pharmacy, Faculty of Biochemistry, Chemistry and Pharmacy, Goethe University, Frankfurt am Main, Germany., Fürst R; Institute of Pharmaceutical Biology, Faculty of Biochemistry, Chemistry and Pharmacy, Goethe University, Frankfurt am Main, Germany; LOEWE Center for Translational Biodiversity Genomics (LOEWE-TBG), Frankfurt am Main, Germany; Pharmaceutical Biology, Department of Pharmacy - Center for Drug Research, Ludwig-Maximilians-Universität München, Munich, Germany. Electronic address: robert.fuerst@cup.lmu.de.
Jazyk: angličtina
Zdroj: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie [Biomed Pharmacother] 2024 Jul; Vol. 176, pp. 116907. Date of Electronic Publication: 2024 Jun 11.
DOI: 10.1016/j.biopha.2024.116907
Abstrakt: The plant alkaloid homoharringtonine (HHT) is a Food and Drug Administration (FDA)-approved drug for the treatment of hematologic malignancies. In addition to its well-established antitumor activity, accumulating evidence attributes anti-inflammatory effects to HHT, which have mainly been studied in leukocytes to date. However, a potential influence of HHT on inflammatory activation processes in endothelial cells, which are a key feature of inflammation and a prerequisite for the leukocyte-endothelial cell interaction and leukocyte extravasation, remains poorly understood. In this study, the anti-inflammatory potential of HHT and its derivative harringtonine (HT) on the TNF-induced leukocyte-endothelial cell interaction was assessed, and the underlying mechanistic basis of these effects was elucidated. HHT affected inflammation in vivo in a murine peritonitis model by reducing leukocyte infiltration and proinflammatory cytokine expression as well as ameliorating abdominal pain behavior. In vitro, HT and HHT impaired the leukocyte-endothelial cell interaction by decreasing the expression of the endothelial cell adhesion molecules intracellular adhesion molecule -1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). This effect was mediated by a bipartite mechanism. While HHT did not affect the prominent TNF-induced pro-inflammatory NF-ĸB signaling cascade, the compound downregulated the VCAM1 mRNA expression in an IRF-1-dependent manner and diminished active ICAM1 mRNA translation as determined by polysome profiling. This study highlights HHT as an anti-inflammatory compound that efficiently hampers the leukocyte-endothelial cell interaction by targeting endothelial activation processes.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
Databáze: MEDLINE
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