Sonidegib potentiates the cancer cells' sensitivity to cytostatic agents by functional inhibition of ABCB1 and ABCG2 in vitro and ex vivo
Language English Country England, Great Britain Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
35314165
DOI
10.1016/j.bcp.2022.115009
PII: S0006-2952(22)00103-4
Knihovny.cz E-resources
- Keywords
- ABC transporter, Cytochrome P450, Non-small cell lung cancer, Pharmacokinetic resistance, Sonidegib,
- MeSH
- ATP Binding Cassette Transporter, Subfamily G, Member 2 metabolism MeSH
- Biphenyl Compounds MeSH
- Drug Resistance, Neoplasm MeSH
- Cytostatic Agents * pharmacology MeSH
- Humans MeSH
- Cell Line, Tumor MeSH
- Neoplasm Proteins metabolism MeSH
- Lung Neoplasms * drug therapy MeSH
- Carcinoma, Non-Small-Cell Lung * drug therapy MeSH
- ATP Binding Cassette Transporter, Subfamily B genetics MeSH
- Hedgehog Proteins metabolism MeSH
- Antineoplastic Agents * pharmacology MeSH
- Pyridines MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- ATP Binding Cassette Transporter, Subfamily G, Member 2 MeSH
- ABCB1 protein, human MeSH Browser
- ABCG2 protein, human MeSH Browser
- Biphenyl Compounds MeSH
- Cytostatic Agents * MeSH
- Neoplasm Proteins MeSH
- ATP Binding Cassette Transporter, Subfamily B MeSH
- Hedgehog Proteins MeSH
- Antineoplastic Agents * MeSH
- Pyridines MeSH
- sonidegib MeSH Browser
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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