Sonidegib potentiates the cancer cells' sensitivity to cytostatic agents by functional inhibition of ABCB1 and ABCG2 in vitro and ex vivo
The result's identifiers
Result code in 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>
Alternative codes found
RIV/00216208:11150/22:10450889 RIV/00179906:_____/22:10450889
Result on the web
<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>
Alternative languages
Result language
angličtina
Original language name
Sonidegib potentiates the cancer cells' sensitivity to cytostatic agents by functional inhibition of ABCB1 and ABCG2 in vitro and ex vivo
Original language description
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.
Czech name
—
Czech description
—
Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
—
OECD FORD branch
30104 - Pharmacology and pharmacy
Result continuities
Project
<a href="/en/project/GJ20-20414Y" target="_blank" >GJ20-20414Y: Study on the role of novel targeted breast and lung anticancer drugs in the phenomenon of pharmacokinetic drug resistance</a><br>
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)
Others
Publication year
2022
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Biochemical Pharmacology
ISSN
0006-2952
e-ISSN
1873-2968
Volume of the periodical
199
Issue of the periodical within the volume
May
Country of publishing house
US - UNITED STATES
Number of pages
11
Pages from-to
115009
UT code for WoS article
000793139700004
EID of the result in the Scopus database
2-s2.0-85126841322