Titel
Lysosomal Sequestration Impairs the Activity of the Preclinical FGFR Inhibitor PD173074
Autor*in
Bernhard Englinger
Institute of Cancer Research and Comprehensive Cancer Center, Department of Medicine I, Medical University of Vienna
Julia Senkiv
Institute of Cancer Research and Comprehensive Cancer Center, Department of Medicine I, Medical University of Vienna
... show all
Abstract
Knowledge of intracellular pharmacokinetics of anticancer agents is imperative for understanding drug efficacy as well as intrinsic and acquired cellular resistance mechanisms. However, the factors driving subcellular drug distribution are complex and poorly understood. Here, we describe for the first time the intrinsic fluorescence properties of the fibroblast growth factor receptor inhibitor PD1703074 as well as utilization of this physicochemical feature to investigate intracellular accumulation and compartmentalization of this compound in human lung cancer cells. Cell-free PD173074 fluorescence, intracellular accumulation and distribution were investigated using analytical chemistry and molecular biology approaches. Analyses on a subcellular scale revealed selective drug accumulation in lysosomes. Coincubation with inhibitors of lysosomal acidification strongly enhanced PD173074-mediated fibroblast growth factor receptor (FGFR) inhibition and cytotoxicity. In conclusion, intrinsic fluorescence enables analysis of molecular factors influencing intracellular pharmacokinetics of PD173074. Lysosome-alkalinizing agents might represent candidates for rational combination treatment, preventing cancer cell-intrinsic PD173074 resistance based on lysosomal trapping.
Stichwort
cancerdrug sequestrationfibroblast growth factor receptorfluorescencelysosomesTKI
Objekt-Typ
Sprache
Englisch [eng]
Persistent identifier
Erschienen in
Titel
Cells
Band
7
Ausgabe
12
Publication
MDPI AG
Erscheinungsdatum
2018
Zugänglichkeit
Rechte
Rechteangabe
© 2018 by the authors
Universität Wien | Universitätsring 1 | 1010 Wien | T
+43-1-4277-0