Lysosomal sequestration of weak base drugs, lysosomal biogenesis, and cell cycle alteration

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61989592%3A15110%2F22%3A73615586" target="_blank" >RIV/61989592:15110/22:73615586 - isvavai.cz</a>

Výsledek na webu

<a href="https://www.sciencedirect.com/science/article/pii/S075333222200717X?via%3Dihub" target="_blank" >https://www.sciencedirect.com/science/article/pii/S075333222200717X?via%3Dihub</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.biopha.2022.113328" target="_blank" >10.1016/j.biopha.2022.113328</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Lysosomal sequestration of weak base drugs, lysosomal biogenesis, and cell cycle alteration

Popis výsledku v původním jazyce

Lysosomes, now known to take part in multiple cellular functions, also respond to various stress stimuli. These include biogenesis in response to nanomolar concentrations of hydrophobic weak-base anticancer drugs. However, since lysosomal stress mediated by accumulation of weak-base drugs at such concentrations has never been proven and these drugs have diverse effects on malignant cells, we investigated whether the interpretation of the data was true. We found that lysosomal accumulation of the drugs daunorubicin, doxorubicin, mitoxantrone, symadex, chloroquine, clomipramine and sunitinib alone, was insufficient to induce lysosomal alkalization i.e., lysosomal stress-mediated biogenesis at nanomolar concentrations. Instead, we found that some of the drugs used induced G2 phase arrest and lysosomal biogenesis that is associated with activation of transcription factor EB (TFEB). Similarly, cantharidin, a control compound that does not belong to the weak base drugs, induced cell cycle arrest in the G2 phase associated with TFEB-driven lysosomal biogenesis. Overall none of the tested drugs caused stress-induced lysosomal biogenesis at nanomolar concentrations. However, daunorubicin, doxorubicin, mitoxantrone, symadex and cantharidin induced a massive block in the G2 phase of the cell cycle which is naturally associated with TFEB-driven lysosomal biogenesis.

Název v anglickém jazyce

Lysosomal sequestration of weak base drugs, lysosomal biogenesis, and cell cycle alteration

Popis výsledku anglicky

Lysosomes, now known to take part in multiple cellular functions, also respond to various stress stimuli. These include biogenesis in response to nanomolar concentrations of hydrophobic weak-base anticancer drugs. However, since lysosomal stress mediated by accumulation of weak-base drugs at such concentrations has never been proven and these drugs have diverse effects on malignant cells, we investigated whether the interpretation of the data was true. We found that lysosomal accumulation of the drugs daunorubicin, doxorubicin, mitoxantrone, symadex, chloroquine, clomipramine and sunitinib alone, was insufficient to induce lysosomal alkalization i.e., lysosomal stress-mediated biogenesis at nanomolar concentrations. Instead, we found that some of the drugs used induced G2 phase arrest and lysosomal biogenesis that is associated with activation of transcription factor EB (TFEB). Similarly, cantharidin, a control compound that does not belong to the weak base drugs, induced cell cycle arrest in the G2 phase associated with TFEB-driven lysosomal biogenesis. Overall none of the tested drugs caused stress-induced lysosomal biogenesis at nanomolar concentrations. However, daunorubicin, doxorubicin, mitoxantrone, symadex and cantharidin induced a massive block in the G2 phase of the cell cycle which is naturally associated with TFEB-driven lysosomal biogenesis.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

—

Návaznosti

S - Specificky vyzkum na vysokych skolach

Rok uplatnění

2022

Kód důvěrnosti údajů

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

Název periodika

BIOMEDICINE &amp; PHARMACOTHERAPY

ISSN

0753-3322

e-ISSN

1950-6007

Svazek periodika

153

Číslo periodika v rámci svazku

září 2022

Stát vydavatele periodika

FR - Francouzská republika

Počet stran výsledku

22

Strana od-do

113328

Kód UT WoS článku

000827236200004

EID výsledku v databázi Scopus

2-s2.0-85133451487