Pharmaceutical Research

, Volume 25, Issue 4, pp 827–835 | Cite as

Constitutive Overexpression of P-glycoprotein, Rather than Breast Cancer Resistance Protein or Organic Cation Transporter 1, Contributes to Acquisition of Imatinib-Resistance in K562 Cells

  • Chie Hirayama
  • Hiroshi Watanabe
  • Reiko Nakashima
  • Takeru Nanbu
  • Akinobu Hamada
  • Akihiko Kuniyasu
  • Hitoshi Nakayama
  • Tatsuya Kawaguchi
  • Hideyuki Saito
Research Paper



The purpose of this study was to investigate the contribution of drug transporters in acquired imatinib-resistance. Specifically, we focused on the efflux transporters, P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), and an influx transporter, organic cation transporter 1 (OCT1).

Materials and methods

We established imatinib-resistant K562 cells (K562/IM). Real-time PCR or Western blot analyses were performed to examine the mRNA or protein levels. Alamar blue method was used in the cytotoxicity assay. The transport activities and intracellular imatinib levels were measured by flow cytometry and HPLC, respectively.


K562/IM displayed a 47-fold increase in resistance to imatinib over the parent K562 cells. Both P-gp and BCRP were overexpressed in K562/IM relative to K562. Furthermore, the intracellular imatinib level was markedly reduced in K562/IM. Interestingly, cyclosporin A, a P-gp inhibitor, but not fumitremorgin C, a BCRP inhibitor, restored both imatinib-sensitivity and the intracellular imatinib level. By contrast, no significant difference in the expression and function of OCT1 was observed between K562/IM and K562.


P-gp, rather than BCRP or OCT1, is partially responsible for the development of imatinib-resistance due to constitutive and functional overexpression, leading to reduced intracellular accumulation of imatinib in K562/IM.

Key words

breast cancer resistance protein drug resistance imatinib organic cation transporter 1 P-glycoprotein 



breast cancer resistance protein




organic cation transporter 1





We thank Dr. Robert W. Robey and Dr. Susan E. Bate at National Cancer Institute (Betheda, MD) for providing FTC and PhA. We also acknowledge Novartis Pharma AG (Basel, Switzerland) for kindly providing imatinib and cyclosporin A.


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Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Chie Hirayama
    • 1
  • Hiroshi Watanabe
    • 1
  • Reiko Nakashima
    • 1
  • Takeru Nanbu
    • 1
  • Akinobu Hamada
    • 1
  • Akihiko Kuniyasu
    • 2
  • Hitoshi Nakayama
    • 2
  • Tatsuya Kawaguchi
    • 3
  • Hideyuki Saito
    • 1
  1. 1.Department of PharmacyKumamoto University HospitalKumamotoJapan
  2. 2.Department of Molecular Cell Function, Graduate School of Medical and Pharmaceutical SciencesKumamoto UniversityKumamotoJapan
  3. 3.Department of Hematology and Infectious DiseasesKumamoto University HospitalKumamotoJapan

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