RESUMO
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) inhibit the function of certain adenosine triphosphate (ATP)-binding cassette transporters, including P-glycoprotein/ABCB1 and breast cancer resistance protein (BCRP)/ABCG2. We previously reported an antagonistic activity of gefitinib towards BCRP. We have now analyzed the effects of erlotinib, another EGFR-TKI, on P-glycoprotein and BCRP. As with gefitinib, erlotinib effectively reversed BCRP-mediated resistance to SN-38 (7-ethyl-10-hydroxycamptothecin) and mitoxantrone. In contrast, we found that erlotinib effectively suppressed P-glycoprotein-mediated resistance to vincristine and paclitaxel, but did not suppress resistance to mitoxantrone and doxorubicin. Conversely, erlotinib appeared to enhance P-glycoprotein-mediated resistance to mitoxantrone in K562/MDR cells. This bidirectional activity of erlotinib was not observed with verapamil, a typical P-glycoprotein inhibitor. Flow cytometric analysis showed that erlotinib co-treatment restored intracellular accumulation of mitoxantrone in K562 cells expressing BCRP, but not in cells expressing P-glycoprotein. Consistently, erlotinib did not inhibit mitoxantrone efflux in K562/MDR cells although it did vincristine efflux in K562/MDR cells and mitoxantrone efflux in K562/BCRP cells. Intravesicular transport assay showed that erlotinib inhibited both P-glycoprotein-mediated vincristine transport and BCRP-mediated estrone 3-sulfate transport. Intriguingly, Lineweaver-Burk plot suggested that the inhibitory mode of erlotinib was a mixed type for P-glycoprotein-mediated vincristine transport whereas it was a competitive type for BCRP-mediated estrone 3-sulfate transport. Collectively, these observations indicate that the pharmacological activity of erlotinib on P-glycoprotein-mediated drug resistance is dependent upon the transporter substrate. These findings will be useful in understanding the pharmacological interactions of erlotinib used in combinational chemotherapy.
