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Nucleoside transporters and human organic cation transporter 1 determine the cellular handling of DNA‐methyltransferase inhibitors
Author(s) -
ArimanyNardi C,
ErrastiMurugarren E,
Minuesa G,
MartinezPicado J,
Gorboulev V,
Koepsell H,
PastorAnglada M
Publication year - 2014
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12748
Subject(s) - efflux , transporter , decitabine , organic cation transport proteins , dna methyltransferase , chemistry , transfection , pharmacology , nucleoside , methyltransferase , nucleoside transporter , membrane transport protein , biochemistry , biology , dna methylation , dna , methylation , gene expression , gene
Background and Purpose Inhibitors of DNA methyltransferases ( DNMT s), such as azacytidine, decitabine and zebularine, are used for the epigenetic treatment of cancer. Their action may depend upon their translocation across the plasma membrane. The aim of this study was to identify transporter proteins contributing to DNMT inhibitor action. Experimental Approach Drug interactions with selected hCNT and hENT proteins were studied in transiently transfected HeLa and MDCK cells. Interaction with human organic cation transporters ( hOCT s) was assessed in transiently transfected HeLa cells and X enopus laevis oocytes.Key Results Zebularine uptake was mediated by hCNT 1, hCNT 3 and hENT 2. Decitabine interacted with but was not translocated by any nucleoside transporter ( NT ) type. hCNT expression at the apical domain of MDCK cells promoted net vectorial flux of zebularine. Neither hOCT 1 nor hOCT 2 transported decitabine, but both were involved in the efflux of zebularine, suggesting these proteins act as efflux transporters. hOCT 1 polymorphic variants, known to alter function, decreased zebularine efflux.Conclusions and Implications This study highlights the influence of human NTs and hOCTs on the pharmacokinetics and pharmacodynamics of selected DNMT inhibitors. As hOCT s may also behave as efflux transporters, they could contribute either to chemoresistance or to chemosensitivity, depending upon the nature of the drug or combination of drugs being used in cancer therapy.