Sonidegib potentiates the cancer cells' sensitivity to cytostatic agents by functional inhibition of ABCB1 and ABCG2 in vitro and ex vivo
Jazyk angličtina Země Anglie, Velká Británie Médium print-electronic
Typ dokumentu časopisecké články, práce podpořená grantem
PubMed
35314165
DOI
10.1016/j.bcp.2022.115009
PII: S0006-2952(22)00103-4
Knihovny.cz E-zdroje
- Klíčová slova
- ABC transporter, Cytochrome P450, Non-small cell lung cancer, Pharmacokinetic resistance, Sonidegib,
- MeSH
- ABC transportér z rodiny G, člen 2 metabolismus MeSH
- bifenylové sloučeniny MeSH
- chemorezistence MeSH
- cytostatické látky * farmakologie MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- nádorové proteiny metabolismus MeSH
- nádory plic * farmakoterapie MeSH
- nemalobuněčný karcinom plic * farmakoterapie MeSH
- P-glykoproteiny genetika MeSH
- proteiny hedgehog metabolismus MeSH
- protinádorové látky * farmakologie MeSH
- pyridiny MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- ABC transportér z rodiny G, člen 2 MeSH
- ABCB1 protein, human MeSH Prohlížeč
- ABCG2 protein, human MeSH Prohlížeč
- bifenylové sloučeniny MeSH
- cytostatické látky * MeSH
- nádorové proteiny MeSH
- P-glykoproteiny MeSH
- proteiny hedgehog MeSH
- protinádorové látky * MeSH
- pyridiny MeSH
- sonidegib MeSH Prohlížeč
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.
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