Afatinib circumvents multidrug resistance via dually inhibiting ATP binding cassette subfamily G member 2 in vitro and in vivo

Multidrug resistance (MDR) to chemotherapeutic drugs is a formidable barrier to the success of cancer chemotherapy. Expressions of ATP-binding cassette (ABC) transporters contribute to clinical MDR phenotype. In this study, we found that afatinib, a small molecule tyrosine kinase inhibitor (TKI) tar...

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Bibliographic Details
Published in:Oncotarget 2014-12, Vol.5 (23), p.11971-11985
Main Authors: Wang, Xiao-Kun, To, Kenneth Kin Wah, Huang, Li-Yan, Xu, Jing-Hong, Yang, Ke, Wang, Fang, Huang, Zhen-Cong, Ye, Sheng, Fu, Li-Wu
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - pharmacology
ATP Binding Cassette Transporter, Sub-Family G, Member 2
ATP-Binding Cassette Transporters - antagonists & inhibitors
Blotting, Western
Cell Line, Tumor
Drug Resistance, Multiple - drug effects
Drug Resistance, Neoplasm - drug effects
Female
Flow Cytometry
Humans
Immunohistochemistry
In Vitro Techniques
Male
Mice
Mice, Inbred BALB C
Neoplasm Proteins - antagonists & inhibitors
Neoplasms, Experimental - drug therapy
Neoplasms, Experimental - metabolism
Quinazolines - pharmacology
Real-Time Polymerase Chain Reaction
Research Paper
Topotecan - pharmacology
Xenograft Model Antitumor Assays
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Summary:Multidrug resistance (MDR) to chemotherapeutic drugs is a formidable barrier to the success of cancer chemotherapy. Expressions of ATP-binding cassette (ABC) transporters contribute to clinical MDR phenotype. In this study, we found that afatinib, a small molecule tyrosine kinase inhibitor (TKI) targeting EGFR, HER-2 and HER-4, reversed the chemoresistance mediated by ABCG2 in vitro, but had no effect on that mediated by multidrug resistance protein ABCB1 and ABCC1. In addition, afatinib, in combination with topotecan, significantly inhibited the growth of ABCG2- overexpressing cell xenograft tumors in vivo. Mechanistic investigations exhibited that afatinib significantly inhibited ATPase activity of ABCG2 and downregulated expression level of ABCG2, which resulted in the suppression of efflux activity of ABCG2 in parallel to the increase of intracellular accumulation of ABCG2 substrate anticancer agents. Taken together, our findings may provide a new and useful combinational therapeutic strategy of afatinib with chemotherapeutical drug for the patients with ABCG2 overexpressing cancer cells.
ISSN:1949-2553
DOI:10.18632/oncotarget.2647