Lysosomal Drug Sequestration Mediated by ABC Transporters and Drug Resistance

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61989592%3A15110%2F25%3A73633478" target="_blank" >RIV/61989592:15110/25:73633478 - isvavai.cz</a>

Výsledek na webu

<a href="https://www.mdpi.com/1999-4923/17/10/1255" target="_blank" >https://www.mdpi.com/1999-4923/17/10/1255</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.3390/pharmaceutics17101255" target="_blank" >10.3390/pharmaceutics17101255</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Lysosomal Drug Sequestration Mediated by ABC Transporters and Drug Resistance

Popis výsledku v původním jazyce

Background: Drug resistance (DR) mediated by ABC transporters in the cytoplasmic membrane has been one of the best studied mechanisms of DR in vitro. More recently, it has also been suggested that ABC transporters expressed on lysosomal membranes could increase the sequestration of anticancer drugs in lysosomes, thereby reducing their concentration at target sites, and causing DR. Unfortunately, convincing evidence that such a DR mechanism actually exists is lacking, even in the case of in vitro experiments. Methods: This hypothetical study using simplified models evaluates the effect of ABC transporter-mediated accumulation of anticancer drugs in lysosomes on their concentration at target sites under standard in vitro conditions. Results: Calculations show that an ABC transporter resident on the plasma membrane must create and maintain a relatively small concentration gradient between extracellular space and the target site to reduce the drug concentration at the target site by, for example, half. In contrast, if a lysosomal ABC transporter is to also halve the concentration of the drug at the target site, then it must create and maintain a huge concentration gradient between lysosomes and target sites. It is very likely that massive accumulation of drugs in lysosomes would have a negative effect on the function of the lysosomes themselves. Conclusions: The results of this hypothetical study strongly suggest that the mechanism of DR mediated by lysosomal ABC transporters is questionable, as it requires enormous accumulation of the drug in lysosomes, which would likely also impair their function. Therefore, it is highly unlikely that this hypothetical DR mechanism could actually be utilized by tumor cells to defend against the cytotoxic effects of chemotherapy in vitro.

Název v anglickém jazyce

Lysosomal Drug Sequestration Mediated by ABC Transporters and Drug Resistance

Popis výsledku anglicky

Background: Drug resistance (DR) mediated by ABC transporters in the cytoplasmic membrane has been one of the best studied mechanisms of DR in vitro. More recently, it has also been suggested that ABC transporters expressed on lysosomal membranes could increase the sequestration of anticancer drugs in lysosomes, thereby reducing their concentration at target sites, and causing DR. Unfortunately, convincing evidence that such a DR mechanism actually exists is lacking, even in the case of in vitro experiments. Methods: This hypothetical study using simplified models evaluates the effect of ABC transporter-mediated accumulation of anticancer drugs in lysosomes on their concentration at target sites under standard in vitro conditions. Results: Calculations show that an ABC transporter resident on the plasma membrane must create and maintain a relatively small concentration gradient between extracellular space and the target site to reduce the drug concentration at the target site by, for example, half. In contrast, if a lysosomal ABC transporter is to also halve the concentration of the drug at the target site, then it must create and maintain a huge concentration gradient between lysosomes and target sites. It is very likely that massive accumulation of drugs in lysosomes would have a negative effect on the function of the lysosomes themselves. Conclusions: The results of this hypothetical study strongly suggest that the mechanism of DR mediated by lysosomal ABC transporters is questionable, as it requires enormous accumulation of the drug in lysosomes, which would likely also impair their function. Therefore, it is highly unlikely that this hypothetical DR mechanism could actually be utilized by tumor cells to defend against the cytotoxic effects of chemotherapy in vitro.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30104 - Pharmacology and pharmacy

Projekt

—

Návaznosti

S - Specificky vyzkum na vysokych skolach

Rok uplatnění

2025

Kód důvěrnosti údajů

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

Název periodika

Pharmaceutics

ISSN

1999-4923

e-ISSN

—

Svazek periodika

17

Číslo periodika v rámci svazku

10

Stát vydavatele periodika

CH - Švýcarská konfederace

Počet stran výsledku

14

Strana od-do

1255

Kód UT WoS článku

001601482900001

EID výsledku v databázi Scopus

2-s2.0-105020054313