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Inhibition of lysyl oxidases improves drug diffusion and increases efficacy of cytotoxic treatment in 3D tumor models

Please always quote using this URN: urn:nbn:de:bvb:20-opus-145109
  • 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 responsibleTumors 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.show moreshow less

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Metadaten
Author: Friedrich Schütze, Florian Röhring, Sandra Vorlová, Sabine Gätzner, Anja Kuhn, Süleyman Ergün, Erik Henke
URN:urn:nbn:de:bvb:20-opus-145109
Document Type:Journal article
Faculties:Medizinische Fakultät / Institut für Klinische Biochemie und Pathobiochemie
Medizinische Fakultät / Institut für Anatomie und Zellbiologie
Medizinische Fakultät / Lehrstuhl für Tissue Engineering und Regenerative Medizin
Language:English
Parent Title (English):Scientific Reports
Year of Completion:2015
Volume:5
Issue:17576
Source:Scientific Reports 5:17576 (2015). DOI: 10.1038/srep17576
DOI:https://doi.org/10.1038/srep17576
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Tag:beta-aminopropionitrile; breast cancer cells; factor binding profiles; human osteosarcoma xenografts; hypoxia inducible factor 1; open-access database; pancreatic cancer; solid tumors; transcapillary pressure gradient; vascular normalization
Release Date:2018/11/05
Licence (German):License LogoCC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International