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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