The Lysosomal Sequestration of Tyrosine Kinase Inhibitors and Drug Resistance.
Identifikátory výsledku
Kód výsledku v 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>
Výsledek na webu
<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>
Alternativní jazyky
Jazyk výsledku
angličtina
Název v původním jazyce
The Lysosomal Sequestration of Tyrosine Kinase Inhibitors and Drug Resistance.
Popis výsledku v původním jazyce
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
Název v anglickém jazyce
The Lysosomal Sequestration of Tyrosine Kinase Inhibitors and Drug Resistance.
Popis výsledku anglicky
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
Klasifikace
Druh
J<sub>imp</sub> - Článek v periodiku v databázi Web of Science
CEP obor
—
OECD FORD obor
10608 - Biochemistry and molecular biology
Návaznosti výsledku
Projekt
<a href="/cs/project/GA17-16614S" target="_blank" >GA17-16614S: Sekvestrace inhibitorů tyrosinových kinas lysozomy a léková resistence u nádorových buněk</a><br>
Návaznosti
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)
Ostatní
Rok uplatnění
2019
Kód důvěrnosti údajů
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Údaje specifické pro druh výsledku
Název periodika
Biomolecules
ISSN
2218-273X
e-ISSN
—
Svazek periodika
2019
Číslo periodika v rámci svazku
9
Stát vydavatele periodika
CH - Švýcarská konfederace
Počet stran výsledku
22
Strana od-do
1-22
Kód UT WoS článku
000502267900036
EID výsledku v databázi Scopus
2-s2.0-85074547323