Journal
BIOCHEMICAL PHARMACOLOGY
Volume 166, Issue -, Pages 120-127Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2019.05.015
Keywords
Tepotinib; Multidrug resistance (MDR); ATP-binding cassette (ABC) transporter; ABCB1; Tyrosine kinase inhibitor
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Funding
- Fund of Guangzhou Science and Technology Program [201707010048]
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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 coadministrating tepotinib with other conventional chemotherapeutic agents to overcome MDR and improve therapeutic effect.
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