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Lapatinib (Tykerb, GW572016) Reverses Multidrug Resistance in Cancer Cells by Inhibiting the Activity of ATP-Binding Cassette Subfamily B Member 1 and G Member 2
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Abstract
Lapatinib is active at the ATP-binding site of tyrosine kinases that are associated with the human epidermal growth factor receptor (Her-1 or ErbB1) and Her-2. It is conceivable that lapatinib may inhibit the function of ATP-binding cassette (ABC) transporters by binding to their ATP-binding sites. The aim of this study was to investigate the ability of lapatinib to reverse tumor multidrug resistance (MDR) due to overexpression of ABC subfamily B member 1 (ABCB1) and ABC subfamily G member 2 (ABCG2) transporters. Our results showed that lapatinib significantly enhanced the sensitivity to ABCB1 or ABCG2 substrates in cells expressing these transporters, although a small synergetic effect was observed in combining lapatinib and conventional chemotherapeutic agents in parental sensitive MCF-7 or S1 cells. Lapatinib alone, however, did not significantly alter the sensitivity of non-ABCB1 or non-ABCG2 substrates in sensitive and resistant cells. Additionally, lapatinib significantly increased the accumulation of doxorubicin or mitoxantrone in ABCB1- or ABCG2-overexpressing cells and inhibited the transport of methotrexate and E217βG by ABCG2. Furthermore, lapatinib stimulated the ATPase activity of both ABCB1 and ABCG2 and inhibited the photolabeling of ABCB1 or ABCG2 with [125I]iodoarylazidoprazosin in a concentration-dependent manner. However, lapatinib did not affect the expression of these transporters at mRNA or protein levels. Importantly, lapatinib also strongly enhanced the effect of paclitaxel on the inhibition of growth of the ABCB1-overexpressing KBv200 cell xenografts in nude mice. Overall, we conclude that lapatinib reverses ABCB1- and ABCG2-mediated MDR by directly inhibiting their transport function. These findings may be useful for cancer combinational therapy with lapatinib in the clinic. [Cancer Res 2008;68(19):7905–14]
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“The ErbB receptor inhibitor lapatinib is an U.S. Food and Drug Administration (FDA) approved drug for the treatment of several HER2 driven cancers and has been shown to also directly inhibit the drug efflux activity of MDR1, both in cancer cells and in in vivo tumor models (36).”
From The drug efflux pump MDR1 promotes intrinsic and acquired resistance to PROTACs in cancer cells (2022) · cites this paper as [36]
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“lapatinib has previously been shown to be a competitive inhibitor of MDR1 both in vitro and in vivo (36)”
From The drug efflux pump MDR1 promotes intrinsic and acquired resistance to PROTACs in cancer cells (2022) · cites this paper as [36]
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Metadata
- Authors
- Dai, C.-L., Tiwari, A. K., Wu, C.-P., Su, X.-D., Wang, S.-R., Liu, D.-G., Ashby, C. R., Huang, Y., Robey, R. W., Liang, Y.-J., Chen, L.-M., Shi, C.-J., Ambudkar, S. V., Chen, Z.-S., & Fu, L.-W.
- Affiliations
- Sun Yat-sen University (CN)
- St. John's University (US)
- National Institutes of Health (US)
- 1State Key Laboratory for Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou, China;
- ORCID
- Venue
- Cancer Research
- Published
- 2008-09-30
- Volume
- 68
- Issue
- 19
- Pages
- 7905-7914
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC2652245
- OpenAlex
- W2098064809
- Cited by
- 386
- References
- 54
- Citations by year
- 2026: 6 · 2025: 8 · 2024: 10 · 2023: 11 · 2022: 22 · 2021: 17 · 2020: 32 · 2019: 26 · 2018: 20 · 2017: 23 · 2016: 22 · 2015: 26 · 2014: 43 · 2013: 16 · 2012: 38
- FWCI
- 11.43
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- St. John's University (579-1110)
- Sun Yat-sen University
- National Institutes of Health
- National Cancer Institute (Z01BC010030, Z01BC010622)
- Topics
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Health Sciences › Medicine › Microbiology (medical) › Antibiotic Resistance in Bacteria
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Keywords
- lapatinib, multidrug resistance reversal, P-glycoprotein, ABCG2, ABC transporters, drug efflux, doxorubicin accumulation, methotrexate transport, paclitaxel, tyrosine kinase inhibitors, combination chemotherapy
- MeSH terms
- ATP Binding Cassette Transporter, Subfamily G, Member 2, Lapatinib, Adenosine Triphosphatases, Animals, Antineoplastic Combined Chemotherapy Protocols, Cells, Cultured, Dose-Response Relationship, Drug, Humans, Mice, Nude, Neoplasm Proteins, Neoplasms, Quinazolines, Transfection, Up-Regulation, Gene Expression Regulation, Neoplastic, Paclitaxel, Drug Resistance, Multiple, ATP Binding Cassette Transporter, Subfamily B, ATP-Binding Cassette Transporters, Drug Resistance, Neoplasm, ATP Binding Cassette Transporter, Subfamily B, Member 1, Xenograft Model Antitumor Assays, Tumor Burden, Mice
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