The tyrosine kinase inhibitor Nintedanib induces lysosomal dysfunctionality: Role of protonation-dependent crystallization processes
- Author(s)
- Elena Mosca, Anja Federa, Christine Pirker, Markus Schosserer, Lisa Liendl, Margret Eckhard, Andy Sombke, Orsolya Dömötör, Dominik Kirchhofer, Gerald Timelthaler, Dina Baier, Patrizia Gurschka, Lisa Gabler, Michael Reithofer, Jia Min Chin, Kareem Elsayad, Bernhard Englinger, Ammar Tahir, Christian R. Kowol, Walter Berger
- Abstract
Nintedanib (NIN), a multi-tyrosine kinase inhibitor clinically approved for idiopathic pulmonary fibrosis and lung cancer, is characterized by protonation-dependent lysosomotropic behavior and appearance of lysosome-specific fluorescence emission properties. Here we investigate whether spontaneous formation of a so far unknown NIN matter within the acidic cell compartment is underlying these unexpected emissive properties and investigate the consequences on lysosome functionality. Lysosomes of cells treated with NIN, but not non-protonatable NIN derivatives, exhibited lysosome-associated birefringence signals co-localizing with the NIN-derived fluorescence emission. Sensitivity of both parameters towards vATPase inhibitors confirmed pH-dependent, spontaneous adoption of novel crystalline NIN structures in lysosomes. Accordingly, NIN crystallization from buffer solutions resulted in formation of multiple crystal polymorphs with pH-dependent fluorescence properties. Cell-free crystals grown at lysosomal-like pH conditions resembled NIN-treated cell lysosomes concerning fluorescence pattern, photobleaching dynamics, and Raman spectra. However, differences in birefringence intensity and FAIM-determined anisotropy, as well as predominant association with (intra)lysosomal membrane structures, suggested formation of a semi-solid NIN crystalline matter in acidic lysosomes. Despite comparable target kinase inhibition, NIN, but not its non-protonatable derivatives, impaired lysosomal functionality, mediated massive cell vacuolization, enhanced autophagy, deregulated lipid metabolism, and induced atypical phospholipidosis. Moreover, NIN exerted distinct phototoxicity, strictly dependent on lysosomal microcrystallization events. The spontaneous formation of NIN crystalline structures was also observable in the gut mucosa of orally NIN-treated mice. Summarizing, the here-described kinase inhibition-independent impact of NIN on lysosomal functionality mediates several of its cell biological activities and might contribute to NIN adverse effects.
- Organisation(s)
- Department of Inorganic Chemistry, Department of Functional Materials and Catalysis, Department of Pharmaceutical Sciences
- External organisation(s)
- Medizinische Universität Wien, University of Natural Resources and Life Sciences, University of Szeged, Research Cluster Translational Cancer Therapy Research, FH Campus Wien, Vienna Doctoral School in Chemistry (DoSChem)
- Journal
- Chemico-Biological Interactions
- Volume
- 403
- ISSN
- 0009-2797
- DOI
- https://doi.org/10.1016/j.cbi.2024.111243
- Publication date
- 11-2024
- Peer reviewed
- Yes
- Austrian Fields of Science 2012
- 301306 Medical molecular biology, 106002 Biochemistry, 301206 Pharmacology
- Keywords
- ASJC Scopus subject areas
- Toxicology
- Sustainable Development Goals
- SDG 3 - Good Health and Well-being
- Portal url
- https://ucrisportal.univie.ac.at/en/publications/98bc0215-c282-4454-b725-451d482ef887