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Clin Cancer Res. 2017 Nov 1;23(21):6697-6707. doi: 10.1158/1078-0432.CCR-16-0667. Epub 2017 Aug 18.

Dasatinib Reversibly Disrupts Endothelial Vascular Integrity by Increasing Non-Muscle Myosin II Contractility in a ROCK-Dependent Manner.

Author information

1
Department of Immunology, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Spain. anna.kreutzman@helsinki.fi cmunozc@salud.madrid.org.
2
Hematology Research Unit Helsinki, Department of Clinical Chemistry and Hematology, University of Helsinki and Helsinki University Central Hospital Comprehensive Cancer Center, Helsinki, Finland.
3
Department of Immunology, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Spain.
4
Universidad Autónoma de Madrid, School of Medicine, Spain.
5
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
6
Department of Hematology, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Madrid, Spain.
7
IBMCC-CIC (CSIC-USAL), Campus Miguel de Unamuno, Salamanca, Spain.

Abstract

Purpose: Dasatinib is a short-acting dual ABL/SRC family tyrosine kinase inhibitor (TKI), which is frequently used to treat chronic myeloid leukemia. Although very effective, patients taking dasatinib often display severe adverse effects, including pleural effusions and increased risk of bleeding primarily in the gastrointestinal tract. The actual causes of these side effects are currently undetermined. We hypothesize that endothelial cells (ECs) that line the inner walls of blood vessels and control the traffic to the underlying tissues might be involved.Experimental Design: The effects of TKIs on ECs were studied by various assays, such as real-time cell impedance measurements, live-cell microscopy, wound healing, Western blot, and an in vivo model.Results: Dasatinib uniquely causes a profound, dose-dependent disorganization of the EC monolayers. Dasatinib promoted the disassembly of cell-cell contacts, altered cell-matrix contacts, and further altered the wound healing. A key observation is that this effect is fully reversible after drug washout. In line with these in vitro observations, intraperitoneal administration of dasatinib to mice caused significant vascular leakage in the intestine. The underlying molecular mechanism of dasatinib-induced reorganization of the actin involves ROCK activation, which increases the amount of the phosphorylation of myosin light chain and consequently activates the non-muscle myosin II.Conclusions: Our data are consistent with a scenario in which dasatinib triggers a transient increase in vascular leakage that probably contributes to adverse effects such as bleeding diathesis and pleural effusions. Clin Cancer Res; 23(21); 6697-707. ©2017 AACR.

PMID:
28821556
DOI:
10.1158/1078-0432.CCR-16-0667
[Indexed for MEDLINE]
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