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The Lysosomal Sequestration of Tyrosine Kinase Inhibitors and Drug Resistance

The Lysosomal sequestration of weak-base anticancer drugs is one putative mechanism for resistance to chemotherapy but it has never been directly proven. We addressed the question of whether the lysosomal sequestration of tyrosine kinase inhibitors (TKIs) itself contributes to the drug resistance in...

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Autores principales: Ruzickova, Eliska, Skoupa, Nikola, Dolezel, Petr, Smith, Dennis A., Mlejnek, Petr
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6921012/
https://www.ncbi.nlm.nih.gov/pubmed/31683643
http://dx.doi.org/10.3390/biom9110675
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author Ruzickova, Eliska
Skoupa, Nikola
Dolezel, Petr
Smith, Dennis A.
Mlejnek, Petr
author_facet Ruzickova, Eliska
Skoupa, Nikola
Dolezel, Petr
Smith, Dennis A.
Mlejnek, Petr
author_sort Ruzickova, Eliska
collection PubMed
description The Lysosomal sequestration of weak-base anticancer drugs is one putative mechanism for resistance to chemotherapy but it has never been directly proven. We addressed the question of whether the lysosomal sequestration of tyrosine kinase inhibitors (TKIs) itself contributes to the drug resistance in vitro. Our analysis indicates that lysosomal sequestration of an anticancer drug can significantly reduce the concentration at target sites, only when it simultaneously decreases its extracellular concentration due to equilibrium, since uncharged forms of weak-base drugs freely diffuse across cellular membranes. Even though the studied TKIs, including imatinib, nilotinib, and dasatinib, were extensively accumulated in the lysosomes of cancer cells, their sequestration was insufficient to substantially reduce the extracellular drug concentration. Lysosomal accumulation of TKIs also failed to affect the Bcr-Abl signaling. Cell pre-treatment with sunitinib significantly enhanced the lysosomal accumulation of the TKIs used; however, without apparent lysosomal biogenesis. Importantly, even increased lysosomal sequestration of TKIs neither decreased their extracellular concentrations nor affected the sensitivity of Bcr-Abl to TKIs. In conclusion, our results clearly show that the lysosomal sequestration of TKIs failed to change their concentrations at target sites, and thus, can hardly contribute to drug resistance in vitro.
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spelling pubmed-69210122019-12-24 The Lysosomal Sequestration of Tyrosine Kinase Inhibitors and Drug Resistance Ruzickova, Eliska Skoupa, Nikola Dolezel, Petr Smith, Dennis A. Mlejnek, Petr Biomolecules Article The Lysosomal sequestration of weak-base anticancer drugs is one putative mechanism for resistance to chemotherapy but it has never been directly proven. We addressed the question of whether the lysosomal sequestration of tyrosine kinase inhibitors (TKIs) itself contributes to the drug resistance in vitro. Our analysis indicates that lysosomal sequestration of an anticancer drug can significantly reduce the concentration at target sites, only when it simultaneously decreases its extracellular concentration due to equilibrium, since uncharged forms of weak-base drugs freely diffuse across cellular membranes. Even though the studied TKIs, including imatinib, nilotinib, and dasatinib, were extensively accumulated in the lysosomes of cancer cells, their sequestration was insufficient to substantially reduce the extracellular drug concentration. Lysosomal accumulation of TKIs also failed to affect the Bcr-Abl signaling. Cell pre-treatment with sunitinib significantly enhanced the lysosomal accumulation of the TKIs used; however, without apparent lysosomal biogenesis. Importantly, even increased lysosomal sequestration of TKIs neither decreased their extracellular concentrations nor affected the sensitivity of Bcr-Abl to TKIs. In conclusion, our results clearly show that the lysosomal sequestration of TKIs failed to change their concentrations at target sites, and thus, can hardly contribute to drug resistance in vitro. MDPI 2019-10-31 /pmc/articles/PMC6921012/ /pubmed/31683643 http://dx.doi.org/10.3390/biom9110675 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Ruzickova, Eliska
Skoupa, Nikola
Dolezel, Petr
Smith, Dennis A.
Mlejnek, Petr
The Lysosomal Sequestration of Tyrosine Kinase Inhibitors and Drug Resistance
title The Lysosomal Sequestration of Tyrosine Kinase Inhibitors and Drug Resistance
title_full The Lysosomal Sequestration of Tyrosine Kinase Inhibitors and Drug Resistance
title_fullStr The Lysosomal Sequestration of Tyrosine Kinase Inhibitors and Drug Resistance
title_full_unstemmed The Lysosomal Sequestration of Tyrosine Kinase Inhibitors and Drug Resistance
title_short The Lysosomal Sequestration of Tyrosine Kinase Inhibitors and Drug Resistance
title_sort lysosomal sequestration of tyrosine kinase inhibitors and drug resistance
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6921012/
https://www.ncbi.nlm.nih.gov/pubmed/31683643
http://dx.doi.org/10.3390/biom9110675
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