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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doaj-f5f6c1ee80514fdcb14acd203105c0f02020-11-24T21:33:39ZengMDPI AGBiomolecules2218-273X2019-10-0191167510.3390/biom9110675biom9110675The Lysosomal Sequestration of Tyrosine Kinase Inhibitors and Drug ResistanceEliska Ruzickova0Nikola Skoupa1Petr Dolezel2Dennis A. Smith3Petr Mlejnek4Department of Anatomy, Faculty of Medicine and Dentistry, Palacky University Olomouc, Hnevotinska 3, Olomouc 77515, Czech RepublicDepartment of Anatomy, Faculty of Medicine and Dentistry, Palacky University Olomouc, Hnevotinska 3, Olomouc 77515, Czech RepublicDepartment of Anatomy, Faculty of Medicine and Dentistry, Palacky University Olomouc, Hnevotinska 3, Olomouc 77515, Czech RepublicHonorary Professor, Department of Chemistry, University of Capetown, Cape Town 7700, South AfricaDepartment of Anatomy, Faculty of Medicine and Dentistry, Palacky University Olomouc, Hnevotinska 3, Olomouc 77515, Czech RepublicThe 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.https://www.mdpi.com/2218-273X/9/11/675tyrosine kinase inhibitorslysosomal sequestrationdrug resistancetarget sitesextralysosomal spaceextracellular space |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Eliska Ruzickova Nikola Skoupa Petr Dolezel Dennis A. Smith Petr Mlejnek |
spellingShingle |
Eliska Ruzickova Nikola Skoupa Petr Dolezel Dennis A. Smith Petr Mlejnek The Lysosomal Sequestration of Tyrosine Kinase Inhibitors and Drug Resistance Biomolecules tyrosine kinase inhibitors lysosomal sequestration drug resistance target sites extralysosomal space extracellular space |
author_facet |
Eliska Ruzickova Nikola Skoupa Petr Dolezel Dennis A. Smith Petr Mlejnek |
author_sort |
Eliska Ruzickova |
title |
The Lysosomal Sequestration of Tyrosine Kinase Inhibitors and Drug Resistance |
title_short |
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_sort |
lysosomal sequestration of tyrosine kinase inhibitors and drug resistance |
publisher |
MDPI AG |
series |
Biomolecules |
issn |
2218-273X |
publishDate |
2019-10-01 |
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. |
topic |
tyrosine kinase inhibitors lysosomal sequestration drug resistance target sites extralysosomal space extracellular space |
url |
https://www.mdpi.com/2218-273X/9/11/675 |
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