The BCRP inhibitor febuxostat enhances the effect of nilotinib by regulation of intracellular concentration
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ORIGINAL ARTICLE
The BCRP inhibitor febuxostat enhances the effect of nilotinib by regulation of intracellular concentration Fumiko Ito1 · Masatomo Miura2 · Yuki Fujioka1 · Maiko Abumiya2 · Takahiro Kobayashi1 · Saori Takahashi3 · Tomoko Yoshioka1 · Yoshihiro Kameoka1,3 · Naoto Takahashi1 Received: 12 July 2020 / Revised: 31 August 2020 / Accepted: 7 September 2020 © Japanese Society of Hematology 2020
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. Keywords Chronic myeloid leukemia · Breast cancer resistant protein (BCRP) · Tyrosine kinase inhibitor (TKI) · Nilotinib · Febuxostat
Introduction Chronic myeloid leukemia (CML) is a clonal myeloproliferative malignancy characterized by abnormal and constant BCR-ABL1 oncogenic tyrosine kinase activity, which is caused by the reciprocal translocation t(9;22). Tyrosine kinase inhibitors (TKIs) are first-line treatments for CML and dramatically improve prognosis. However, some patients suffer relapse and progression of disease due to the development of resistance to TKI therapy. Although one of most * Naoto Takahashi [email protected]‑u.ac.jp 1
Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, 1‑1‑1 Hondo, Akita, Akita 010‑8543, Japan
2
Department of Pharmacy, Akita University Hospital, Akita, Japan
3
Clinical Research Promotion and Support Center, Akita University Hospital, Akita, Japan
important mechanisms of resistance is the acquisition of point mutations in the BCR-ABL kinase domain, such as T315I, half of TKI-resistant CML patients do not have a mutation in the BCR-ABL domain, suggesting that another mechanism can enable CML cells to escape the pharmacolog
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