The small-molecule kinase inhibitor ceritinib, unlike imatinib, causes a significant disturbance of lipid membrane integrity: A combined experimental and MD study.

Autor: Fischer M; Leipzig University, Institute for Medical Physics and Biophysics, Härtelstr. 16-18, D-04107 Leipzig, Germany., Luck M; Humboldt University Berlin, Department of Biology, Invalidenstr. 42, D-10115 Berlin, Germany., Werle M; Humboldt University Berlin, Department of Biology, Invalidenstr. 42, D-10115 Berlin, Germany., Vogel A; Leipzig University, Institute for Medical Physics and Biophysics, Härtelstr. 16-18, D-04107 Leipzig, Germany., Bashawat M; Humboldt University Berlin, Department of Biology, Invalidenstr. 42, D-10115 Berlin, Germany., Ludwig K; Freie Universität Berlin, Research Center for Electron Microscopy and Core Facility BioSupraMol, Institute of Chemistry and Biochemistry, Fabeckstr. 36a, D-14195 Berlin, Germany., Scheidt HA; Leipzig University, Institute for Medical Physics and Biophysics, Härtelstr. 16-18, D-04107 Leipzig, Germany. Electronic address: holger.scheidt@medizin.uni-leipzig.de., Müller P; Humboldt University Berlin, Department of Biology, Invalidenstr. 42, D-10115 Berlin, Germany. Electronic address: peter.mueller.3@rz.hu-berlin.de.
Jazyk: angličtina
Zdroj: Chemistry and physics of lipids [Chem Phys Lipids] 2023 Nov; Vol. 257, pp. 105351. Date of Electronic Publication: 2023 Oct 18.
DOI: 10.1016/j.chemphyslip.2023.105351
Abstrakt: Ceritinib and imatinib are small-molecule protein kinase inhibitors which are applied as therapeutic agents against various diseases. The fundamentals of their clinical use, i.e. their pharmacokinetics as well as the mechanisms of the inhibition of the respective kinases, are relatively well studied. However, the interaction of the drugs with membranes, which can be a possible cause of side effects, has hardly been investigated so far. Therefore, we have characterized the interaction of both drugs with lipid membranes consisting of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) in the absence and in the presence of cholesterol. For determining the membrane impact of both drugs on a molecular level, different experimental (NMR, ESR, fluorescence) and theoretical (MD simulations) approaches were applied. The data show that ceritinib, in contrast to imatinib, interacts more effectively with membranes significantly affecting various physico-chemical membrane parameters like membrane order and transmembrane permeation of polar solutes. The pronounced membrane impact of ceritinib can be explained by a strong affinity of the drug towards POPC which competes with the POPC-cholesterol interaction by that attenuating the ordering effect of cholesterol. The data are relevant for understanding putative toxic and cytotoxic side effects of these drugs such as the triggering of cell lysis or apoptosis.
Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest with the contents of this article.
(Copyright © 2023 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: