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

Article Details

Citation

Ito F, Miura M, Fujioka Y, Abumiya M, Kobayashi T, Takahashi S, Yoshioka T, Kameoka Y, Takahashi N

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

Int J Hematol. 2021 Jan;113(1):100-105. doi: 10.1007/s12185-020-03000-x. Epub 2020 Oct 6.

PubMed ID
33025461 [ View in PubMed
]
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.

DrugBank Data that Cites this Article

Drug Transporters
DrugTransporterKindOrganismPharmacological ActionActions
FebuxostatATP-binding cassette sub-family G member 2ProteinHumans
No
Inhibitor
Details
Drug Interactions
DrugsInteraction
Abemaciclib
Febuxostat
The excretion of Abemaciclib can be decreased when combined with Febuxostat.
Afatinib
Febuxostat
The excretion of Afatinib can be decreased when combined with Febuxostat.
Allopurinol
Febuxostat
The excretion of Allopurinol can be decreased when combined with Febuxostat.
Apixaban
Febuxostat
The excretion of Apixaban can be decreased when combined with Febuxostat.
Binimetinib
Febuxostat
The excretion of Binimetinib can be decreased when combined with Febuxostat.