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PMID: 22411867 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Dasatinib inhibits proinflammatory functions of mature human neutrophils.

Blood ·Vol. 119 ·No. 21 ·2012-05-24 ·Pages 4981-91

Futosi K, Németh T, Pick R, Vántus T, Walzog B, Mócsai A

Abstract

Dasatinib is a tyrosine kinase inhibitor used to treat imatinib-resistant chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. At present, little is known about how dasatinib influences nonmalignant cells. In the present study, we tested the effect of dasatinib on functional responses of normal mature human neutrophils. Dasatinib completely blocked integrin- and Fc-receptor-mediated neutrophil functions, with the lowest IC(50) values below 10nM under serum-free conditions. Dasatinib caused a partial inhibition of neutrophil responses triggered by G-protein-coupled receptors and had a moderate effect on neutrophil responses triggered by microbial compounds. Whereas dasatinib inhibited neutrophil chemotaxis under static conditions in 2 dimensions, it did not affect migration under flow conditions or in 3-dimensional environments. Dasatinib did not have any major effect on phagocytosis or killing of bacteria by neutrophils. Adhesion of human neutrophils in the presence of whole serum was significantly inhibited by 50-100nM dasatinib, which corresponds to the reported serum concentrations in dasatinib-treated patients. Finally, ex vivo adhesion of mouse peripheral blood neutrophils was strongly reduced after oral administration of 5 mg/kg of dasatinib. Those results suggest that dasatinib treatment may affect the proinflammatory functions of mature neutrophils and raise the possibility that dasatinib-related compounds may provide clinical benefit in neutrophil-mediated inflammatory diseases.

MeSH Terms
Animals Anti-Inflammatory Agents/pharmacology Antineoplastic Agents/pharmacology Cell Adhesion/drug effects,immunology Cell Respiration/drug effects Cells, Cultured Dasatinib Down-Regulation/drug effects Drug Evaluation, Preclinical Humans Inflammation/metabolism,prevention & control Inflammation Mediators/antagonists & inhibitors,metabolism,physiology Mice Mice, Inbred C57BL Neutrophil Activation/drug effects,physiology Neutrophils/drug effects,immunology,metabolism,physiology Pyrimidines/pharmacology Respiratory Burst/drug effects,physiology Thiazoles/pharmacology
Chemicals
Anti-Inflammatory Agents Antineoplastic Agents Inflammation Mediators Pyrimidines Thiazoles Dasatinib
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Futosi Krisztina
Department of Physiology, Semmelweis University School of Medicine, Budapest, Hungary.
Németh Tamás
Pick Robert
Vántus Tibor
Walzog Barbara
Mócsai Attila
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Article Info
Journal
Blood
Abbr.
Blood
ISSN
1528-0020
DOI
10.1182/blood-2011-07-369041
Published
2012-05-24
Epub
2012-00-12
Pages
4981-91
Language
English
Region
United States
NLM ID
7603509
PMCID
PMC3367900
Subset
IM
Grants
Wellcome Trust · United Kingdom
European Research Council · 206283 · International
Wellcome Trust · 087782 · United Kingdom
Corrections
CommentIn
PMID: 22627592
External Links
PubMed source DOI: 10.1182/blood-2011-07-369041 PMC Full Text View journal details
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