Substrate-dependent bidirectional modulation of P-glycoprotein-mediated drug resistance by erlotinib.
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Noguchi K, Kawahara H, Kaji A, Katayama K, Mitsuhashi J, Sugimoto Y
Substrate-dependent bidirectional modulation of P-glycoprotein-mediated drug resistance by erlotinib.
Cancer Sci. 2009 Sep;100(9):1701-7. doi: 10.1111/j.1349-7006.2009.01213.x. Epub 2009 May 12.
- PubMed ID
- 19493273 [ View in PubMed]
- Abstract
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.
DrugBank Data that Cites this Article
- Drug Transporters
Drug Transporter Kind Organism Pharmacological Action Actions Erlotinib ATP-binding cassette sub-family G member 2 Protein Humans UnknownInhibitorDetails Erlotinib P-glycoprotein 1 Protein Humans UnknownSubstrateInhibitorDetails Estrone P-glycoprotein 1 Protein Humans UnknownSubstrateInducerDetails Gefitinib ATP-binding cassette sub-family G member 2 Protein Humans UnknownSubstrateInhibitorDetails Mitoxantrone ATP-binding cassette sub-family G member 2 Protein Humans UnknownSubstrateDetails Mitoxantrone P-glycoprotein 1 Protein Humans UnknownSubstrateInhibitorInducerDetails Paclitaxel P-glycoprotein 1 Protein Humans UnknownSubstrateInhibitorDetails Vincristine P-glycoprotein 1 Protein Humans UnknownSubstrateInhibitorInducerDetails