title: Inhibition of Lysyl Oxidases Improves Drug Diffusion and Increases Efficacy of Cytotoxic Treatment in 3D Tumor Models.
abstract: Tumors are characterized by a rigid, highly cross-linked extracellular matrix (ECM), which impedes homogeneous drug distribution and potentially protects malignant cells from exposure to therapeutics. Lysyl oxidases are major contributors to tissue stiffness and the elevated expression of these enzymes observed in most cancers might influence drug distribution and efficacy. We examined the effect of lysyl oxidases on drug distribution and efficacy in 3D in vitro assay systems. In our experiments elevated lysyl oxidase activity was responsible for reduced drug diffusion under hypoxic conditions and consequently impaired cytotoxicity of various chemotherapeutics. This effect was only observed in 3D settings but not in 2D-cell culture, confirming that lysyl oxidases affect drug efficacy by modification of the ECM and do not confer a direct desensitizing effect. Both drug diffusion and efficacy were strongly enhanced by inhibition of lysyl oxidases. The results from the in vitro experiments correlated with tumor drug distribution in vivo, and predicted response to therapeutics in murine tumor models. Our results demonstrate that lysyl oxidase activity modulates the physical barrier function of ECM for small molecule drugs influencing their therapeutic efficacy. Targeting this process has the potential to significantly enhance therapeutic efficacy in the treatment of malignant diseases.
authors.affiliation: Institute of Anatomy and Cell Biology II, Universität Würzburg Koellikerstrasse 6, Würzburg, 97070, Germany.
authors.forename: Friedrich
authors.initials: F
authors.lastname: Schütze
authors.affiliation: Institute of Anatomy and Cell Biology II, Universität Würzburg Koellikerstrasse 6, Würzburg, 97070, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Röhrig
authors.affiliation: Institute of Clinical Biochemistry and Pathobiochemistry, Universitätsklinikum Würzburg Josef-Schneider-Strasse 2, Würzburg, 97080, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Vorlová
authors.affiliation: Institute of Tissue Engineering, Universität Würzburg Roentgenring 11, Würzburg, 97070, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Gätzner
authors.affiliation: Institute of Anatomy and Cell Biology II, Universität Würzburg Koellikerstrasse 6, Würzburg, 97070, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Kuhn
authors.affiliation: Institute of Anatomy and Cell Biology II, Universität Würzburg Koellikerstrasse 6, Würzburg, 97070, Germany.
authors.forename: Süleyman
authors.initials: S
authors.lastname: Ergün
authors.affiliation: Institute of Anatomy and Cell Biology II, Universität Würzburg Koellikerstrasse 6, Würzburg, 97070, Germany.|Graduate School for Life Science, Universität Würzburg Josef-Schneider-Strasse 2, Würzburg, 97080, Germany.
authors.forename: Erik
authors.initials: E
authors.lastname: Henke
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D051379:Mice; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000201:enzymology*; D008249:Protein-Lysine 6-Oxidase / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D009363:Neoplasm Proteins; D008249:Protein-Lysine 6-Oxidase