Sonidegib potentiates the cancer cells' sensitivity to cytostatic agents by functional inhibition of ABCB1 and ABCG2 in vitro and ex vivo

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11160%2F22%3A10450889" target="_blank" >RIV/00216208:11160/22:10450889 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00216208:11150/22:10450889 RIV/00179906:_____/22:10450889

Výsledek na webu

<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=WQ.EdSiS5W" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=WQ.EdSiS5W</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.bcp.2022.115009" target="_blank" >10.1016/j.bcp.2022.115009</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Sonidegib potentiates the cancer cells' sensitivity to cytostatic agents by functional inhibition of ABCB1 and ABCG2 in vitro and ex vivo

Popis výsledku v původním jazyce

Sonidegib (LDE-225) is a Hedgehog pathway inhibitor used for the therapy of basal cell carcinoma. In addition, the drug is a subject of clinical trials for the treatment of other solid tumors including non-small cell lung cancer (NSCLC). In this study, we explored the potential of sonidegib to act as a perpetrator of drug-drug interactions (DDIs) and modulator of transporter-and enzyme-mediated multidrug resistance (MDR). First, we found that transport functions of ABCB1 and ABCG2 were effectively inhibited by sonidegib in accumulation studies. In contrast, the drug did not cause fluctuations in mRNA levels of tested efflux transporters. In drug combination assays, sonidegib synergistically enhanced the cytotoxicity of daunorubicin and mitoxantrone in ABCB1-and ABCG2-overexpressing cells, respectively. Notably, similar phenomena were also observed in explant tumor cultures derived from NSCLC-suffering patients. In addition, the anticancer effects of sonidegib were not hampered by the expression of the ABC transporters associated with MDR. Last, sonidegib had no significant influence on the activity of CYP3A4 isoform in vitro. In summary, our work suggests that sonidegib can be considered a potential perpetrator of clinical DDIs on ABCB1 and ABCG2. After in vivo evaluation, its chemosensitizing properties might be projected into efficient and safe treatment regimen for the clinical management of NSCLC patients with high ABCB1/ABCG2 expression.

Název v anglickém jazyce

Sonidegib potentiates the cancer cells' sensitivity to cytostatic agents by functional inhibition of ABCB1 and ABCG2 in vitro and ex vivo

Popis výsledku anglicky

Sonidegib (LDE-225) is a Hedgehog pathway inhibitor used for the therapy of basal cell carcinoma. In addition, the drug is a subject of clinical trials for the treatment of other solid tumors including non-small cell lung cancer (NSCLC). In this study, we explored the potential of sonidegib to act as a perpetrator of drug-drug interactions (DDIs) and modulator of transporter-and enzyme-mediated multidrug resistance (MDR). First, we found that transport functions of ABCB1 and ABCG2 were effectively inhibited by sonidegib in accumulation studies. In contrast, the drug did not cause fluctuations in mRNA levels of tested efflux transporters. In drug combination assays, sonidegib synergistically enhanced the cytotoxicity of daunorubicin and mitoxantrone in ABCB1-and ABCG2-overexpressing cells, respectively. Notably, similar phenomena were also observed in explant tumor cultures derived from NSCLC-suffering patients. In addition, the anticancer effects of sonidegib were not hampered by the expression of the ABC transporters associated with MDR. Last, sonidegib had no significant influence on the activity of CYP3A4 isoform in vitro. In summary, our work suggests that sonidegib can be considered a potential perpetrator of clinical DDIs on ABCB1 and ABCG2. After in vivo evaluation, its chemosensitizing properties might be projected into efficient and safe treatment regimen for the clinical management of NSCLC patients with high ABCB1/ABCG2 expression.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30104 - Pharmacology and pharmacy

Projekt

<a href="/cs/project/GJ20-20414Y" target="_blank" >GJ20-20414Y: Studium role nových cílených léčiv určených pro terapii nádorů prsu a plic ve fenoménu farmakokinetické lékové rezistence</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2022

Kód důvěrnosti údajů

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

Název periodika

Biochemical Pharmacology

ISSN

0006-2952

e-ISSN

1873-2968

Svazek periodika

199

Číslo periodika v rámci svazku

May

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

11

Strana od-do

115009

Kód UT WoS článku

000793139700004

EID výsledku v databázi Scopus

2-s2.0-85126841322