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.
Highlights
Intrinsic and acquired multidrug resistance (MDR) to chemotherapeutic drugs is a main obstacle for the successful cancer chemotherapy
Of interest is the observation that ABCG2 has been considered as a determinant of side population (SP) cells which are highly enriched in cancer stem cells (CSCs), and appears to play a critical role in the resistance of CSCs [7, 8]
To investigate whether afatinib could potentiate the efficacy of chemotherapeutic agents in various resistant cells, MTT assay was first used to detect the cytotoxicity of afatinib alone
Summary
Intrinsic and acquired multidrug resistance (MDR) to chemotherapeutic drugs is a main obstacle for the successful cancer chemotherapy. It is well established that ABCB1 (P-glycoprotein, MDR1), ABCC1 (multidrug resistance associated protein 1, MRP1) and ABCG2 (breast cancer resistance protein, BCRP) are involved in the active extrusion of anticancer drugs from cells [2]. There is emerging evidence that the expression of ABCG2 is associated with a poor clinical response to chemotherapy [3,4,5,6]. Inhibition or down-regulation of ABCG2 may be a valid approach to reverse ABCG2-mediated drug resistance and to improve the clinical efficacy of cancer chemotherapy
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