Tepotinib reverses ABCB1-mediated multidrug resistance in cancer cells.
Biochem Pharmacol
; 166: 120-127, 2019 08.
Article
en En
| MEDLINE
| ID: mdl-31078601
ABSTRACT
Overexpression of ABCB1 transporters plays a crucial role in mediating multidrug resistance (MDR). Therefore, it is important to inhibit ABCB1 activity in order to maintain an effective intracellular level of chemotherapeutic drugs. Tepotinib is a MET tyrosine kinase inhibitor with potential anticancer effect and it is currently in clinical trials. In this study, we investigated whether tepotinib could antagonize ABC transporters-mediated MDR. Our results suggest that tepotinib significantly reversed ABCB1-mediated MDR but not ABCG2- or ABCC1-mediated MDR. Mechanistic studies show that tepotinib significantly reversed ABCB1-mediated MDR by attenuating the efflux activity of ABCB1 transporter. The ATPase assay showed that tepotinib inhibited the ATPase activity of ABCB1 in a concentration-dependent manner. Furthermore, treatment with tepotinib did not change protein expression or subcellular localization of ABCB1. Docking analysis indicated that tepotinib interacted with the drug-binding site of the ABCB1 transporter. Our study provides a potential chemotherapeutic strategy of co-administrating tepotinib with other conventional chemotherapeutic agents to overcome MDR and improve therapeutic effect.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Piridazinas
/
Pirimidinas
/
Resistencia a Múltiples Medicamentos
/
Resistencia a Antineoplásicos
/
Antineoplásicos
Límite:
Humans
Idioma:
En
Revista:
Biochem Pharmacol
Año:
2019
Tipo del documento:
Article
País de afiliación:
Estados Unidos