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The BCRP inhibitor febuxostat enhances the effect of nilotinib by regulation of intracellular concentration

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Abstract

Nilotinib is a substrate of the breast cancer resistance protein (BCRP), which is a drug efflux transporter encoded by ABCG2 and regulates the pharmacokinetics of its substrates. We investigated the interaction between nilotinib and BCRP in chronic myeloid leukemia (CML) cells. An imatinib-resistant K562 cell line (K562/IM-R) treated with nilotinib was analyzed for BCRP expression, proliferation, apoptosis, and intracellular nilotinib concentration. K562/IM-R cells cultured with tyrosine kinase inhibitors (TKIs) showed an increased cell count and retained viability, whereas the growth of parental K562 cells was severely inhibited, suggesting that BCRP is involved in developing resistance to TKIs. Nilotinib-treated K562/IM-R cells showed a reduction in apoptosis; however, febuxostat pretreatment resulted in increased apoptosis. The intracellular concentration of nilotinib in K562/IM-R cells was significantly reduced compared to that in parental K562 cells, and febuxostat-pretreated K562/IM-R cells showed an increased intracellular nilotinib level compared to cells without pretreatment. The reduction in nilotinib levels caused by BCRP in CML cells might play a crucial role in resistance to TKIs. Moreover, febuxostat, as a BCRP inhibitor, could enhance nilotinib sensitivity, and combination therapy with nilotinib and febuxostat may represent a promising strategy for treatment of CML.

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Acknowledgements

We would like to thank Editage (https://www.editage.com) for English editing.

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Authors and Affiliations

  1. Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, Akita, 010-8543, Japan

    Fumiko Ito, Yuki Fujioka, Takahiro Kobayashi, Tomoko Yoshioka, Yoshihiro Kameoka & Naoto Takahashi

  2. Department of Pharmacy, Akita University Hospital, Akita, Japan

    Masatomo Miura & Maiko Abumiya

  3. Clinical Research Promotion and Support Center, Akita University Hospital, Akita, Japan

    Saori Takahashi & Yoshihiro Kameoka

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  1. Fumiko Ito
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  2. Masatomo Miura
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  4. Maiko Abumiya
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  5. Takahiro Kobayashi
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  6. Saori Takahashi
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  8. Yoshihiro Kameoka
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  9. Naoto Takahashi
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Correspondence to Naoto Takahashi.

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Conflict of interest

Dr. Naoto Takahashi reports that he has received Grants and speaker’s fees from Novartis Pharmaceuticals, speaker’s fees from Bristol Myers Squibb, Grants and speaker’s fees from Pfizer, Grants and speaker’s fees from Otsuka Pharmaceutical, Grants from Kyowa Hakko Kirin, Grants from Astellas Pharma, Grants from Chugai Pharmaceutical, Grants from Asahi Kasei Pharma, Grants from Ono Pharmaceutical, and Grants from Eisai Pharmaceuticals, outside of the submitted work. The remaining authors declare that they have no conflicts of interest.

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Ito, F., Miura, M., Fujioka, Y. et al. The BCRP inhibitor febuxostat enhances the effect of nilotinib by regulation of intracellular concentration. Int J Hematol 113, 100–105 (2021). https://doi.org/10.1007/s12185-020-03000-x

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  • DOI: https://doi.org/10.1007/s12185-020-03000-x

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