Format

Send to

Choose Destination
Oncotarget. 2014 Dec 15;5(23):11971-85.

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

Author information

1
State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
2
School of Pharmacy, The Chinese University of Hong Kong, Hong Kong, P.R. China.
3
First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.

Abstract

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.

PMID:
25436978
PMCID:
PMC4322967
DOI:
10.18632/oncotarget.2647
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Impact Journals, LLC Icon for PubMed Central
Loading ...
Support Center