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

Cancer Chemotherapy and Pharmacology
Vijaya L DamarajuMichael B Sawyer

Abstract

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). 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 [(3)H]adenine or 1 µM [(3)H]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. 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...Continue Reading

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Oct 31, 2013·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Vijaya L DamarajuMichael B Sawyer
Nov 14, 2013·Biochemistry and Cell Biology = Biochimie Et Biologie Cellulaire·Vijaya L DamarajuMichael B Sawyer
Dec 19, 2014·Molecular Cancer Therapeutics·Vijaya L DamarajuMichael B Sawyer

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Citations

Aug 5, 2017·Biological & Pharmaceutical Bulletin·Katsuhisa Inoue

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