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Inhibition of sodium-independent and sodium-dependent nucleobase transport activities by tyrosine kinase inhibitors

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Abstract

Purpose

Effects of tyrosine kinase inhibitors (TKIs) on equilibrative nucleobase transport (ENBT) and sodium-dependent nucleobase transport (SNBT) activities were investigated in normal human renal proximal tubule epithelial cells (hRPTECs) and in pig kidney cell line (LLC-PK1).

Methods

Uptake assays were performed by assessing accumulation of radiolabeled nucleobases over time into hRPTECs or LLC-PK1 cell lines which express ENBT and SNBT activities, respectively. Dose–response curves for inhibition of 1 µM [3H]adenine or 1 µM [3H]hypoxanthine were examined in hRPTECs and in LLC-PK1 cells with varying TKI concentrations (0–100 µM) to calculate the IC50 values (mean ± S.E) for inhibition.

Results

Gefitinib inhibited ENBT activity with an IC50 value of 0.7 µM, thus indicating strong interactions of ENBT with gefitinib in hRPTECs. Erlotinib > sorafenib > imatinib > sunitinib inhibited ENBT with IC50 values of 15, 40, 60, 78 µM, respectively, whereas dasatinib, lapatinib, and vandetanib were not inhibitory at concentrations >100 µM. Similar studies in LLC-PK1 cells which exhibit SNBT activity showed that vandetanib was the most potent inhibitor followed by sorafenib > erlotinib > gefitinib > sunitinib > imatinib with IC50 values of 14, 25, 28, 40, 47, 94 µM, respectively, whereas dasatinib and lapatinib were not inhibitory at concentrations >100 µM.

Conclusions

These results suggest for the first time inhibition of both ENBT and SNBT transport activities by TKIs. These results suggest that it is important to consider potential effects on combination regimens using TKIs with nucleobase drugs such as 5-FU in cancer treatment.

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Fig. 1

Abbreviations

NTs:

Nucleoside transporters

H:

Human

ENTs:

Equilibrative nucleoside transporters

CNTs:

Concentrative nucleoside transporters

VEGFR:

Vascular endothelial growth factor receptor

EGFR:

Epidermal growth factor receptor

ENBT:

Equilibrative nucleobase transport

SNBT:

Sodium-dependent nucleobase transport

IC50 :

Concentration of test compound that inhibited transport of nucleobase into cells by 50 % relative to control cells

TKIs:

Tyrosine kinase inhibitors

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Acknowledgments

Funding for this work was provided by a grant from Alberta Innovates health solutions to M.B.S.

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Authors and Affiliations

  1. Department of Oncology, University of Alberta, Edmonton, AB, Canada

    Vijaya L. Damaraju, Carol E. Cass & Michael B. Sawyer

  2. Department of Medical Oncology, Cross Cancer Institute, 11560 University Avenue NW, Edmonton, AB, T6G 1Z2, Canada

    Michelle Kuzma & Michael B. Sawyer

Authors
  1. Vijaya L. Damaraju
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  2. Michelle Kuzma
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  3. Carol E. Cass
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  4. Michael B. Sawyer
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Correspondence to Michael B. Sawyer.

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Damaraju, V.L., Kuzma, M., Cass, C.E. et al. Inhibition of sodium-independent and sodium-dependent nucleobase transport activities by tyrosine kinase inhibitors. Cancer Chemother Pharmacol 76, 1093–1098 (2015). https://doi.org/10.1007/s00280-015-2859-8

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  • DOI: https://doi.org/10.1007/s00280-015-2859-8

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