Abstract
ABCB1-mediated multidrug resistance (MDR) remains a major obstacle to successful chemotherapy in ovarian cancer. Herein, afatinib at nontoxic concentrations significantly reversed ABCB1-mediated MDR in ovarian cancer cells in vitro (p < 0.05). Combining paclitaxel and afatinib caused tumor regressions and tumor necrosis in A2780T xenografts in vivo. More interestingly, unlike reversible TKIs, afatinib had a distinctive dual-mode action. Afatinib not only inhibited the efflux function of ABCB1, but also attenuated its expression transcriptionally via down-regulation of PI3K/AKT and MAPK/p38-dependent activation of NF-κB. Furthermore, apart from a substrate binding domain, afatinib could also bind to an ATP binding domain of ABCB1 through forming hydrogen bonds with Gly533, Gly534, Lys536 and Ala560 sites. Importantly, mutations in these four binding sites of ABCB1 and the tyrosine kinase domain of EGFR were not correlated with the reversal activity of afatinib on MDR. Given that afatinib is a clinically approved drug, our results suggest combining afatinib with chemotherapeutic drugs in ovarian cancer. This study can facilitate the rediscovery of superior MDR reversal agents from molecular targeted drugs to provide a more effective and safer way of resensitizing MDR.
Highlights
ABCB1-mediated multidrug resistance (MDR) remains a major obstacle to successful chemotherapy in the clinic [1,2,3,4,5]
More than 90% of the cells were viable with a concentration up to 0.5 μM afatinib for A2780 cells, 2.5 μM for A2780T cells, 0.5 μM for A2780/ABCB1 ̄ cells and 1.25 μM for A2780T/ABCB1 ̄ cells
Knockdown of ABCB1 in A2780T and SKOV3-DDP cells further enhanced the reversal effect of afatinib on MDR. These results indicated that afatinib could reverse the MDR to ABCB1 substrate drugs in ABCB1-overexpressing ovarian cancer cells
Summary
ABCB1-mediated MDR remains a major obstacle to successful chemotherapy in the clinic [1,2,3,4,5]. ABCB1 is highly expressed in human ovarian cancer and its overexpression is correlated inversely with a benign response to chemotherapy and good clinical prognosis [6, 7]. For this reason, tremendous efforts have been made to discover or synthesize ABCB1 inhibitors to reverse ABCB1-mediated MDR in the past decades [8,9,10,11]. It is reported that several TKIs could only statically inhibit the efflux function of ABCB1 and enhance the anticancer efficacy of chemotherapeutic drugs [13,14,15,16,17]. The binding model between TKIs and ABCB1 was rarely investigated
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