Tepotinib reverses ABCB1-mediated multidrug resistance in cancer cells.
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Wu ZX, Teng QX, Cai CY, Wang JQ, Lei ZN, Yang Y, Fan YF, Zhang JY, Li J, Chen ZS
Tepotinib reverses ABCB1-mediated multidrug resistance in cancer cells.
Biochem Pharmacol. 2019 Aug;166:120-127. doi: 10.1016/j.bcp.2019.05.015. Epub 2019 May 9.
- PubMed ID
- 31078601 [ View in PubMed]
- 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.
DrugBank Data that Cites this Article
- Drugs
- Drug Transporters
Drug Transporter Kind Organism Pharmacological Action Actions Tepotinib P-glycoprotein 1 Protein Humans NoSubstrateInhibitorDetails - Drug Interactions
Drugs Interaction Integrate drug-drug
interactions in your softwareAbemaciclibTepotinib The serum concentration of Abemaciclib can be increased when it is combined with Tepotinib. AmbrisentanTepotinib The serum concentration of Ambrisentan can be increased when it is combined with Tepotinib. ApixabanTepotinib The serum concentration of Apixaban can be increased when it is combined with Tepotinib. AvanafilTepotinib The serum concentration of Avanafil can be increased when it is combined with Tepotinib. AxitinibTepotinib The serum concentration of Axitinib can be increased when it is combined with Tepotinib.