Tepotinib is a novel tyrosine kinase inhibitor recently approved for the treatment of non-small cell lung cancer (NSCLC). In this study, we evaluated the tepotinib's potential to perpetrate pharmacokinetic drug interactions and modulate multidrug resistance (MDR). Accumulation studies showed that tepotinib potently inhibits ABCB1 and ABCG2 efflux transporters, which was confirmed by molecular docking. In addition, tepotinib inhibited several recombinant cytochrome P450 (CYP) isoforms with varying potency. In subsequent drug combination experiments, tepotinib synergistically reversed daunorubicin and mitoxantrone resistance in cells with ABCB1 and ABCG2 overexpression, respectively. Remarkably, MDR-modulatory properties were confirmed in ex vivo explants derived from NSCLC patients. Furthermore, we demonstrated that anticancer effect of tepotinib is not influenced by the presence of ABC transporters associated with MDR, although monolayer transport assays designated it as ABCB1 substrate. Finally, tested drug was observed to have negligible effect on the expression of clinically relevant drug efflux transporters and CYP enzymes. In conclusion, our findings provide complex overview on the tepotinib's drug interaction profile and suggest a promising novel therapeutic strategy for future clinical investigations.

• MeSH
• ABC transportéry antagonisté a inhibitory   MeSH
• chemorezistence účinky léků   MeSH
• cytostatické látky farmakologie   MeSH
• lékové interakce * MeSH
• lidé MeSH
• mnohočetná léková rezistence účinky léků   MeSH
• nádory plic farmakoterapie   metabolismus   patologie   MeSH
• nemalobuněčný karcinom plic farmakoterapie   metabolismus   patologie   MeSH
• piperidiny farmakologie   MeSH
• protinádorové látky farmakologie   MeSH
• pyridaziny farmakologie   MeSH
• pyrimidiny farmakologie   MeSH
• techniky in vitro MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Increasing evidence suggests that apoptosis of tubular cells and renal inflammation mainly determine the outcome of sepsis-associated acute kidney injury (AKI). The study aim was to investigate the molecular mechanism involved in the renoprotective effects of simvastatin in endotoxin (lipopolysaccharide, LSP)-induced AKI. A sepsis model was established by intraperitoneal injection of a single non-lethal LPS dose after short-term simvastatin pretreatment. The severity of the inflammatory injury was expressed as renal damage scores (RDS). Apoptosis of tubular cells was detected by Terminal deoxynucleotidyl transferase-mediated dUTP Nick End Labeling (TUNEL assay) (apoptotic DNA fragmentation, expressed as an apoptotic index, AI) and immunohistochemical staining for cleaved caspase-3, cytochrome C, and anti-apoptotic Bcl-xL and survivin. We found that endotoxin induced severe renal inflammatory injury (RDS = 3.58 ± 0.50), whereas simvastatin dose-dependently prevented structural changes induced by LPS. Furthermore, simvastatin 40 mg/kg most profoundly attenuated tubular apoptosis, determined as a decrease of cytochrome C, caspase-3 expression, and AIs (p  <  0.01 vs. LPS). Conversely, simvastatin induced a significant increase of Bcl-XL and survivin, both in the strong inverse correlations with cleaved caspase-3 and cytochrome C. Our study indicates that simvastatin has cytoprotective effects against LPS-induced tubular apoptosis, seemingly mediated by upregulation of cell-survival molecules, such as Bcl-XL and survivin, and inhibition of the mitochondrial cytochrome C and downstream caspase-3 activation.

• MeSH
• akutní poškození ledvin chemicky indukované   farmakoterapie   genetika   patologie   MeSH
• apoptóza účinky léků   MeSH
• cytochromy c genetika   MeSH
• endotoxiny toxicita   MeSH
• epitelové buňky účinky léků   patologie   MeSH
• krysa rodu rattus MeSH
• ledvinové kanálky účinky léků   patologie   MeSH
• ledviny účinky léků   zranění   metabolismus   patologie   MeSH
• lidé MeSH
• lipopolysacharidy toxicita   MeSH
• protein bcl-X genetika   MeSH
• simvastatin farmakologie   MeSH
• viabilita buněk účinky léků   MeSH
• zánět chemicky indukované   farmakoterapie   genetika   patologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH