BACKGROUND AND PURPOSE
Inhibitors of DNA methyltransferases (DNMTs), 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 ...»»»»
BACKGROUND AND PURPOSE
Inhibitors of DNA methyltransferases (DNMTs), 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 (hOCTs) was assessed in transiently transfected HeLa cells and Xenopus
laevis oocytes.
KEY RESULTS
Zebularine uptake was mediated by hCNT1, hCNT3 and hENT2. 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 hOCT1 nor hOCT2 transported decitabine, but both were involved in the efflux of zebularine, suggesting
these proteins act as efflux transporters. hOCT1 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 hOCTs 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.^^^^