Journal
BIOCHEMICAL PHARMACOLOGY
Volume 158, Issue -, Pages 274-285Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2018.10.028
Keywords
Ulixertinib; Multidrug resistance; ATP-binding cassette (ABC) transporter; ABCB1; ABCG2
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Funding
- St. John's University Research Seed Grant [579-1110-7002]
- National Natural Science Foundation of China [81673464]
- Major Project of Tianjin for New Drug Development [17ZXXYSY00050]
- Postgraduate Innovation Fund of '13th Five-Year comprehensive investment', Tianjin Medical University [YJSCX201712]
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Ulixertinib (BVD-523) is a highly potent, selective, and reversible ERK1/2 inhibitor and is currently in clinical development for the treatment of advanced solid tumors. In this study, we investigated whether ulixertinib could antagonize multidrug resistance (MDR) mediated by ATP-binding cassette (ABC) transporters. The results showed that ulixertinib, at non-toxic concentrations, significantly reversed ATP-binding cassette subfamily B member 1 (ABCB1)- and ATP-binding cassette subfamily G member 2 (ABCG2)-mediated MDR. In ABCB1-overexpressing cells, ulixertinib antagonized MDR by attenuating the efflux function of ABCB1. Similarly, in ABCG2-overexpressing cells, ulixertinib inhibited the efflux activity of ABCG2 and reversed resistance to substrate anticancer drugs. The reversal effects of ulixertinib were not related to the down-regulation or change of subcellular localization of ABCB1 or ABCG2. Mechanistic investigations revealed that ulixertinib stimulated the ATPase activity of both ABCB1 and ABCG2 in a concentration-dependent manner, and the in silico docking study predicted that ulixertinib could interact with the substrate-binding sites of both ABCB1 and ABCG2. Our finding provides a clue into a novel treatment strategy: a combination of ulixertinib with anticancer drugs to attenuate MDR mediated by ABCB1 or ABCG2 in cancer cells overexpressing these transporters.
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