The Lysosomal Sequestration of Tyrosine Kinase Inhibitors and Drug Resistance.

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61989592%3A15110%2F19%3A73597945" target="_blank" >RIV/61989592:15110/19:73597945 - isvavai.cz</a>

Result on the web

<a href="https://www.mdpi.com/2218-273X/9/11/675/htm" target="_blank" >https://www.mdpi.com/2218-273X/9/11/675/htm</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.3390/biom9110675" target="_blank" >10.3390/biom9110675</a>

Result language

angličtina

Original language name

The Lysosomal Sequestration of Tyrosine Kinase Inhibitors and Drug Resistance.

Original language 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

Czech name

—

Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

10608 - Biochemistry and molecular biology

Project

<a href="/en/project/GA17-16614S" target="_blank" >GA17-16614S: Lysosomal sequestration of tyrosine kinase inhibitors and drug resistance in cancer cells</a><br>

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year

2019

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Biomolecules

ISSN

2218-273X

e-ISSN

—

Volume of the periodical

2019

Issue of the periodical within the volume

9

Country of publishing house

CH - SWITZERLAND

Number of pages

22

Pages from-to

1-22

UT code for WoS article

000502267900036

EID of the result in the Scopus database

2-s2.0-85074547323