Dacomitinib antagonizes multidrug resistance (MDR) in cancer cells by inhibiting the efflux activity of ABCB1 and ABCG2 transporters
Abstract
The development of multidrug resistance (MDR) to chemotherapy remains a major challenge in the treatment of cancer. Numerous mechanisms have been recognized that cause MDR, but one of the most important mechanisms is overexpression of adenosine triphosphate (ATP)-binding cassette (ABC) transporters, through which the efflux of various anticancer drugs against their concentration gradients is powered by ATP. In recent years, small molecular tyrosine kinase inhibitors (TKIs) have been developed for treatment in various human cancers overexpressing epidermal growth factor receptor (EGFR). At the same time, some TKIs have been shown to be capable of inhibiting ABC transporter-mediated MDR. Dacomitinib (PF-00299804) is a second generation, irreversible TKI, which has shown positive anticancer activities in some preclinical and clinical trials. As many TKIs are substrates or inhibitors of ABC transporters, this study investigates whether dacomitinib could interact with ABC subfamily members that mediate MDR, including ABCB1 (P-gp), ABCG2 (BCRP) and ABCC1 (MRP1). The results showed that dacomitinib at 1.0 μM significantly reversed drug resistance mediated by ABCB1 and ABCG2, but not ABCC1, doing so by antagonizing the drug efflux function in ABCB1- and ABCG2-overexpressing cell lines. The reversal effect on ABCB1-overexpressing cells is more potent than that on ABCG2-overexpressing cells. In addition, dacomitinib at reversal concentration affected neither the protein expression level nor the localization of ABCB1 and ABCG2. Therefore, the mechanisms of this modulating effect are likely to be the following: first, as an inhibitor of ABCB1 or ABCG2 transporters, dacomitinib binds to drug-substrate site in transmembrane domains (TMD) stably in a noncompetitive manner; or second, dacomitinib inhibits ATPase activity and maintains the stability of TMD conformation in a concentration-dependent manner thereby inhibiting the drug efflux function of ABCB1 or ABCG2 transporter. This study provides a useful combinational therapeutic strategy with dacomitinib and substrates of ABCB1 and/or ABCG2 transporters in ABCB1- or ABCG2-overexpressing cancers.
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The multidrug resistance phenomenon is mainly attributed to over-expression of the ATP-binding cassette transporter family in cancer cells, including ABCG1, ABCC1 and ABCG2.
“The phenomenon was mainly attributed to the over-expression of ATP-binding cassette (ABC) transporter family in cancer cells, including ABCG1, ABCC1 and ABCG2.8–10”
Multidrug resistance contributes to reduced sensitivity of cancer cells to chemotherapeutic drugs, mainly owing to over-expression of drug efflux transporters.
“Multidrug resistance (MDR) has emerged to be a major hindrance in cancer therapy, which contributes to the reduced sensitivity of cancer cells toward chemotherapeutic drugs mainly owing to the over-expression of drug efflux transporters.”
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- Authors
- Fan, Y.-F., Zhang, W., Zeng, L., Lei, Z.-N., Cai, C.-Y., Gupta, P., Yang, D.-H., Cui, Q., Qin, Z.-D., Chen, Z.-S., & Trombetta, L. D.
- Affiliations
- Weifang Medical University (CN)
- St. John's University (US)
- Corresponding author
- Chen, Zhe-Sheng
- Trombetta, Louis D.
- Venue
- Cancer Letters
- Publisher
- Elsevier BV
- Published
- 2018-05
- Volume
- 421
- Pages
- 186-198
- ISSN
- 0304-3835 (ISSN-L)
- OpenAlex
- W2782736845
- Cited by
- 116
- References
- 45
- Citations by year
- 2026: 6 · 2025: 4 · 2024: 13 · 2023: 13 · 2022: 17 · 2021: 13 · 2020: 20 · 2019: 15 · 2018: 15
- FWCI
- 6.00
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Letters (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Alabama at Birmingham
- National Cancer Institute (R15CA143701)
- Topics
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Medicine › Antibiotic Resistance in Bacteria
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Keywords
- dacomitinib, multidrug resistance, P-glycoprotein, ABCG2, MRP1, ABC transporters, drug efflux, tyrosine kinase inhibitors, epidermal growth factor receptor, drug resistance reversal, transmembrane domain, ATPase activity, non-competitive inhibition, combination therapy
- MeSH terms
- ATP Binding Cassette Transporter, Subfamily G, Member 2, Humans, Neoplasm Proteins, Drug Resistance, Multiple, ATP Binding Cassette Transporter, Subfamily B, Drug Resistance, Neoplasm, ATP-Binding Cassette, Sub-Family C Proteins, Cell Line, Tumor, Quinazolinones, Molecular Docking Simulation
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