Substrate-dependent bidirectional modulation of P-glycoprotein-mediated drug resistance by erlotinib

Kohji Noguchi, Haruka Kawahara, Airi Kaji, Kazuhiro Katayama, Junko Mitsuhashi, Yoshikazu Sugimoto

Research output: Contribution to journalArticle

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Abstract

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFRTKIs) 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 BCRPmediated 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-glycoproteinmediated 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.

Original languageEnglish
Pages (from-to)1701-1707
Number of pages7
JournalCancer Science
Volume100
Issue number9
DOIs
Publication statusPublished - 2009 Sep

Fingerprint

P-Glycoprotein
Drug Resistance
Mitoxantrone
irinotecan
Breast Neoplasms
K562 Cells
Vincristine
Proteins
Erlotinib Hydrochloride
Pharmacology
Verapamil
Paclitaxel
Epidermal Growth Factor Receptor
Protein-Tyrosine Kinases
Doxorubicin
Adenosine Triphosphate
Drug Therapy

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Substrate-dependent bidirectional modulation of P-glycoprotein-mediated drug resistance by erlotinib. / Noguchi, Kohji; Kawahara, Haruka; Kaji, Airi; Katayama, Kazuhiro; Mitsuhashi, Junko; Sugimoto, Yoshikazu.

In: Cancer Science, Vol. 100, No. 9, 09.2009, p. 1701-1707.

Research output: Contribution to journalArticle

Noguchi, Kohji ; Kawahara, Haruka ; Kaji, Airi ; Katayama, Kazuhiro ; Mitsuhashi, Junko ; Sugimoto, Yoshikazu. / Substrate-dependent bidirectional modulation of P-glycoprotein-mediated drug resistance by erlotinib. In: Cancer Science. 2009 ; Vol. 100, No. 9. pp. 1701-1707.
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