Nucleoside transporters and human organic cation transporter 1 determine the cellular handling of DNA-methyltransferase inhibitors.
OBJECTIVE
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.


METHODS
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.


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
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.
Departament de Bioquímica i Biologia Molecular, Institut de Biomedicina, Universitat de Barcelona (IBUB) & National Biomedical Research Institute on Liver and Gastrointestinal Diseaes (CIBERehd), Barcelona, Spain.
C
C
Arimany-Nardi
E
E
Errasti-Murugarren
G
G
Minuesa
J
J
Martinez-Picado
V
V
Gorboulev
H
H
Koepsell
M
M
Pastor-Anglada
D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D001692:Biological Transport; D002470:Cell Survival / Q000187:drug effects; D003562:Cytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors*; D000077209:Decitabine; D004285:Dogs; D006367:HeLa Cells; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D033703:Nucleoside Transport Proteins / Q000235:genetics / Q000378:metabolism*; D009865:Oocytes / Q000378:metabolism; D027702:Organic Cation Transporter 1 / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis
D033703:Nucleoside Transport Proteins; D027702:Organic Cation Transporter 1; D003562:Cytidine; D000077209:Decitabine; C009131:pyrimidin-2-one beta-ribofuranoside; D015254:DNA Modification Methylases; D001374:Azacitidine