An Endoplasmic Reticulum Specific Pro-amplifier of Reactive Oxygen Species in Cancer Cells

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61389030%3A_____%2F21%3A00550039" target="_blank" >RIV/61389030:_____/21:00550039 - isvavai.cz</a>

Výsledek na webu

<a href="http://doi.org/10.1002/anie.202100054" target="_blank" >http://doi.org/10.1002/anie.202100054</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1002/anie.202100054" target="_blank" >10.1002/anie.202100054</a>

Jazyk výsledku

angličtina

Název v původním jazyce

An Endoplasmic Reticulum Specific Pro-amplifier of Reactive Oxygen Species in Cancer Cells

Popis výsledku v původním jazyce

The folding and export of proteins and hydrolysis of unfolded proteins are disbalanced in the endoplasmic reticulum (ER) of cancer cells, leading to so-called ER stress. Agents further augmenting this effect are used as anticancer drugs including clinically approved proteasome inhibitors bortezomib and carfilzomib. However, these drugs can affect normal cells, which also rely strongly on ER functions, leading, for example, to accumulation of reactive oxygen species (ROS). To address this problem, we have developed ER-targeted prodrugs activated only in cancer cells in the presence of elevated ROS amounts. These compounds are conjugates of cholic acid with N-alkylaminoferrocene-based prodrugs. We confirmed their accumulation in the ER of cancer cells, their anticancer efficacy, and cancer cell specificity. These prodrugs induce ER stress, attenuate mitochondrial membrane potential, and generate mitochondrial ROS leading to cell death via necrosis. We also demonstrated that the new prodrugs are activated in vivo in Nemeth-Kellner lymphoma (NK/Ly) murine model.

Název v anglickém jazyce

An Endoplasmic Reticulum Specific Pro-amplifier of Reactive Oxygen Species in Cancer Cells

Popis výsledku anglicky

The folding and export of proteins and hydrolysis of unfolded proteins are disbalanced in the endoplasmic reticulum (ER) of cancer cells, leading to so-called ER stress. Agents further augmenting this effect are used as anticancer drugs including clinically approved proteasome inhibitors bortezomib and carfilzomib. However, these drugs can affect normal cells, which also rely strongly on ER functions, leading, for example, to accumulation of reactive oxygen species (ROS). To address this problem, we have developed ER-targeted prodrugs activated only in cancer cells in the presence of elevated ROS amounts. These compounds are conjugates of cholic acid with N-alkylaminoferrocene-based prodrugs. We confirmed their accumulation in the ER of cancer cells, their anticancer efficacy, and cancer cell specificity. These prodrugs induce ER stress, attenuate mitochondrial membrane potential, and generate mitochondrial ROS leading to cell death via necrosis. We also demonstrated that the new prodrugs are activated in vivo in Nemeth-Kellner lymphoma (NK/Ly) murine model.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10601 - Cell biology

Projekt

—

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2021

Kód důvěrnosti údajů

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

Název periodika

Angewandte Chemie - International Edition

ISSN

1433-7851

e-ISSN

1521-3773

Svazek periodika

60

Číslo periodika v rámci svazku

20

Stát vydavatele periodika

DE - Spolková republika Německo

Počet stran výsledku

5

Strana od-do

11158-11162

Kód UT WoS článku

000637988500001

EID výsledku v databázi Scopus

2-s2.0-85104053100