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Branebrutinib (BMS-986195), a Bruton’s Tyrosine Kinase Inhibitor, Resensitizes P-Glycoprotein-Overexpressing Multidrug-Resistant Cancer Cells to Chemotherapeutic Agents

Authors :
Chung-Pu Wu
Megumi Murakami
Yu-Shan Wu
Ya-Chen Chi
Sung-Han Hsiao
Yang-Hui Huang
Tai-Ho Hung
Suresh V. Ambudkar
Source :
Frontiers in Cell and Developmental Biology, Vol 9 (2021)
Publication Year :
2021
Publisher :
Frontiers Media S.A., 2021.

Abstract

The overexpression of P-glycoprotein (P-gp/ABCB1), an ATP-binding cassette (ABC) drug transporter, often contributes to the development of multidrug resistance (MDR) in cancer cells. P-gp mediates the ATP hydrolysis-dependent efflux of a wide range of chemotherapeutic agents out of cancer cells, thereby reducing the intracellular drug accumulation and decreasing the chemosensitivity of these multidrug-resistant cancer cells. Studies with tyrosine kinase inhibitors (TKIs) in P-gp-overexpressing cells have shown that certain TKIs could reverse MDR mediated by P-gp, while some TKIs are transported by P-gp. In the present work, we explored the prospect of repositioning branebrutinib (BMS-986195), a highly selective inhibitor of Bruton’s tyrosine kinase (BTK), to resensitize P-gp-overexpressing multidrug-resistant cancer cells to chemotherapeutic agents. Our results demonstrated that branebrutinib is capable of reversing P-gp-mediated MDR at sub-toxic concentrations, most likely by directly inhibiting the drug transport function of P-gp. Our findings were supported by the result of branebrutinib stimulating the ATPase activity of P-gp in a concentration-dependent manner and the in silico study of branebrutinib binding to the substrate-binding pocket of P-gp. In addition, we found that branebrutinib is equally cytotoxic to drug-sensitive parental cell lines and the respective P-gp-overexpressing multidrug-resistant variants, suggesting that it is unlikely that the overexpression of P-gp in cancer cells plays a significant role in reduced susceptibility or resistance to branebrutinib. In summary, we discovered an additional pharmacological action of branebrutinib against the activity of P-gp, which should be investigated further in future drug combination studies.

Details

Language :
English
ISSN :
2296634X
Volume :
9
Database :
Directory of Open Access Journals
Journal :
Frontiers in Cell and Developmental Biology
Publication Type :
Academic Journal
Accession number :
edsdoj.9abef849ae4f428dacb77846b8f6b34d
Document Type :
article
Full Text :
https://doi.org/10.3389/fcell.2021.699571