title: The interaction of sorafenib and regorafenib with membranes is modulated by their lipid composition.
abstract: Sorafenib and regorafenib are small-molecule kinase inhibitors approved for the treatment of locally recurrent or metastatic, progressive, differentiated thyroid carcinoma, renal cell carcinoma, and hepatocellular carcinoma (sorafenib) and of colorectal cancer (regorafenib). As of now, the mechanisms, which are responsible for their antitumor activities, are not completely understood. Given the lipophilic nature of the molecules, it can be hypothesized that the pharmacological impact is mediated by the interaction with cellular membranes as it is true for many pharmacologically active molecules. However, an interaction of sorafenib or regorafenib with lipid membranes has not yet been investigated in detail. Here, we characterized the interaction of both drugs with lipid membranes by applying a variety of biophysical approaches including nuclear magnetic resonance, electron spin resonance, and fluorescence spectroscopy. We found that sorafenib and regorafenib bind to lipid membranes by inserting into the lipid-water interface of the bilayer. This membrane embedding causes a disturbance of bilayer structure leading to an increased permeability of the membrane for polar molecules. One approach shows that the extent of the effects depends on the membrane lipid composition underlining a particular role of phosphatidylcholine and cholesterol. Our data for the first time characterize the impact of sorafenib and regorafenib on the lipid membrane structure and dynamics, which may contribute to a better understanding of their effectiveness in the treatment of malignancies as well as of their side effects.
authors: Humboldt-Universität zu Berlin, Department of Biology, Invalidenstr. 42, D-10115 Berlin, Germany.
authors: Ivan
authors: I
authors: Haralampiev
authors: Leipzig University, Institute for Medical Physics and Biophysics, Härtelstr, 16-18, D-04107 Leipzig, Germany.
authors: Holger A
authors: HA
authors: Scheidt
authors: Leipzig University, Institute for Medical Physics and Biophysics, Härtelstr, 16-18, D-04107 Leipzig, Germany.
authors: Tobias
authors: T
authors: Abel
authors: Humboldt-Universität zu Berlin, Department of Biology, Invalidenstr. 42, D-10115 Berlin, Germany.
authors: Madlen
authors: M
authors: Luckner
authors: Humboldt-Universität zu Berlin, Department of Biology, Invalidenstr. 42, D-10115 Berlin, Germany.
authors: Andreas
authors: A
authors: Herrmann
authors: Leipzig University, Institute for Medical Physics and Biophysics, Härtelstr, 16-18, D-04107 Leipzig, Germany. Electronic address: daniel.huster@medizin.uni-leipzig.de.
authors: Daniel
authors: D
authors: Huster
authors: Humboldt-Universität zu Berlin, Department of Biology, Invalidenstr. 42, D-10115 Berlin, Germany. Electronic address: peter.mueller.3@rz.hu-berlin.de.
authors: Peter
authors: P
authors: Müller
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D001205:Ascorbic Acid / Q000737:chemistry; D002462:Cell Membrane / Q000737:chemistry / Q000187:drug effects; D002463:Cell Membrane Permeability; D002784:Cholesterol / Q000737:chemistry*; D004227:Dithionite / Q000737:chemistry; D007700:Kinetics; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D010084:Oxidation-Reduction; D010671:Phenylurea Compounds / Q000737:chemistry* / Q000494:pharmacology; D010713:Phosphatidylcholines / Q000737:chemistry*; D010714:Phosphatidylethanolamines / Q000737:chemistry*; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology; D000077157:Sorafenib; D013113:Spin Labels; D013194:Staining and Labeling / Q000379:methods; D053835:Unilamellar Liposomes / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D010713:Phosphatidylcholines; D010714:Phosphatidylethanolamines; D011725:Pyridines; D013113:Spin Labels; D053835:Unilamellar Liposomes; C057561:1-palmitoyl-2-oleoylphosphatidylethanolamine; D004227:Dithionite; C559147:regorafenib; D009536:Niacinamide; D002784:Cholesterol; D000077157:Sorafenib; D001205:Ascorbic Acid; C028694:1-palmitoyl-2-oleoylphosphatidylcholine
keywords: Lipid vesicles; Lipid-drug interaction; Membrane structure; Order parameter; Regorafenib; Sorafenib