Cells 2018, 7(12), 259; https://doi.org/10.3390/cells7120259
Lysosomal Sequestration Impairs the Activity of the Preclinical FGFR Inhibitor PD173074
Bernhard Englinger 1
, Sebastian Kallus 2,3, Julia Senkiv 1,4, Anna Laemmerer 1, Patrick Moser 1, Lisa Gabler 1, Diana Groza 1, Christian R. Kowol 2,3, Petra Heffeter 1,3, Michael Grusch 1 and Walter Berger 1,3,*
, Sebastian Kallus 2,3, Julia Senkiv 1,4, Anna Laemmerer 1, Patrick Moser 1, Lisa Gabler 1, Diana Groza 1, Christian R. Kowol 2,3, Petra Heffeter 1,3, Michael Grusch 1 and Walter Berger 1,3,*
1
Institute of Cancer Research and Comprehensive Cancer Center, Department of Medicine I, Medical University of Vienna, A-1090 Vienna, Austria
2
Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, A-1090 Vienna, Austria
3
Research Cluster "Translational Cancer Therapy Research", A-1090 Vienna, Austria
4
Institute of Cell Biology, National Academy of Sciences of Ukraine, 79005 Lviv, Ukraine
*
Author to whom correspondence should be addressed.
Received: 28 September 2018 / Revised: 3 December 2018 / Accepted: 4 December 2018 / Published: 8 December 2018
(This article belongs to the Special Issue Receptor Tyrosine Kinases in Health and Disease)
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. View Full-TextKeywords:
cancer; drug sequestration; fibroblast growth factor receptor; fluorescence; lysosomes; TKI
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Englinger, B.; Kallus, S.; Senkiv, J.; Laemmerer, A.; Moser, P.; Gabler, L.; Groza, D.; Kowol, C.R.; Heffeter, P.; Grusch, M.; Berger, W. Lysosomal Sequestration Impairs the Activity of the Preclinical FGFR Inhibitor PD173074. Cells 2018, 7, 259.
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