Lysosomal-mediated drug resistance – Fact or illusion?

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61989592%3A15110%2F24%3A73624591" target="_blank" >RIV/61989592:15110/24:73624591 - isvavai.cz</a>

Výsledek na webu

<a href="https://www.sciencedirect.com/science/article/pii/S104366182300381X?via%3Dihub" target="_blank" >https://www.sciencedirect.com/science/article/pii/S104366182300381X?via%3Dihub</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.phrs.2023.107025" target="_blank" >10.1016/j.phrs.2023.107025</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Lysosomal-mediated drug resistance – Fact or illusion?

Popis výsledku v původním jazyce

pH gradients across cell membranes affect the intracellular distribution of hydrophobic weak-base anticancer agents. This significantly reduces their availability at target sites, reducing cytotoxic effect and leading to drug resistance. This hypothetical in vitro study evaluates the impact of two important pH gradients on the intracellular distribution of such drugs in tumor cells.Calculations with simplified models clearly show that even a relatively small pH gradient between cytosol and extracellular environment can dramatically reduce the intracellular concentration of weak-base drugs. This is only slightly affected by the pKa or number of cells. However, if the later is enormous and the volume ratio between extracellular environment and target site (cytosol) decreases significantly, the pH gradient has little effect on the drug concentration at target site. In contrast, even a large pH gradient between lysosomes and cytosol has only marginal impact on the intracellular drug distribution. The effects of the drug pKa or number of cells are also small here. Only extremely acidic lysosomal pH or enormous lysosome size have substantial impact on the target site concentration of weak-base drugs, although the significance of these effects is questionable.In conclusion, the volume ratio between the drug “trapping” and target sites is a crucial factor in the ability of pH gradients to change target site drug concentrations. Accordingly, the pH gradient between cytosol and extracellular environment has a much greater impact on the intracellular distribution of hydrophobic weak-base drugs than that between lysosomes and cytosol under standard conditions in laboratory experiments.

Název v anglickém jazyce

Lysosomal-mediated drug resistance – Fact or illusion?

Popis výsledku anglicky

pH gradients across cell membranes affect the intracellular distribution of hydrophobic weak-base anticancer agents. This significantly reduces their availability at target sites, reducing cytotoxic effect and leading to drug resistance. This hypothetical in vitro study evaluates the impact of two important pH gradients on the intracellular distribution of such drugs in tumor cells.Calculations with simplified models clearly show that even a relatively small pH gradient between cytosol and extracellular environment can dramatically reduce the intracellular concentration of weak-base drugs. This is only slightly affected by the pKa or number of cells. However, if the later is enormous and the volume ratio between extracellular environment and target site (cytosol) decreases significantly, the pH gradient has little effect on the drug concentration at target site. In contrast, even a large pH gradient between lysosomes and cytosol has only marginal impact on the intracellular drug distribution. The effects of the drug pKa or number of cells are also small here. Only extremely acidic lysosomal pH or enormous lysosome size have substantial impact on the target site concentration of weak-base drugs, although the significance of these effects is questionable.In conclusion, the volume ratio between the drug “trapping” and target sites is a crucial factor in the ability of pH gradients to change target site drug concentrations. Accordingly, the pH gradient between cytosol and extracellular environment has a much greater impact on the intracellular distribution of hydrophobic weak-base drugs than that between lysosomes and cytosol under standard conditions in laboratory experiments.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30104 - Pharmacology and pharmacy

Projekt

—

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2024

Kód důvěrnosti údajů

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

Název periodika

PHARMACOLOGICAL RESEARCH

ISSN

1043-6618

e-ISSN

1096-1186

Svazek periodika

199

Číslo periodika v rámci svazku

January 2024

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

3

Strana od-do

107025

Kód UT WoS článku

001143368600001

EID výsledku v databázi Scopus

2-s2.0-85180360444