Nucleoside transporters and human organic cation transporter 1 determine the cellular handling of DNA-methyltransferase inhibitors
Por:
Arimany-Nardi, C, Errasti-Murugarren, E, Minuesa, G, Martinez-Picado, J, Gorboulev, V, Koepsell, H and Pastor-Anglada, M
Publicada:
1 ago 2014
Categoría:
Pharmacology
Resumen:
Background and PurposeInhibitors 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 ApproachDrug 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 ResultsZebularine 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 ImplicationsThis 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.
Filiaciones:
Arimany-Nardi, C:
Univ Barcelona IBUB, Inst Biomed, Dept Bioquim & Biol Mol, Barcelona, Spain
Natl Biomed Res Inst Liver & Gastrointestinal Dis, Barcelona, Spain
Errasti-Murugarren, E:
Univ Barcelona IBUB, Inst Biomed, Dept Bioquim & Biol Mol, Barcelona, Spain
Natl Biomed Res Inst Liver & Gastrointestinal Dis, Barcelona, Spain
Minuesa, G:
Univ Autonoma Barcelona, Hosp Univ Germans Trias & Pujol, AIDS Res Inst IRSICAIXA, Badalona, Spain
:
Univ Autonoma Barcelona, Hosp Univ Germans Trias & Pujol, AIDS Res Inst IRSICAIXA, Badalona, Spain
ICREA, Barcelona, Spain
Univ Vic, Vic, Spain
Gorboulev, V:
Univ Wurzburg, Sch Med, Dept Anat & Cell Biol, D-97070 Wurzburg, Germany
Koepsell, H:
Univ Wurzburg, Sch Med, Dept Anat & Cell Biol, D-97070 Wurzburg, Germany
Univ Wurzburg, Julius von Sachs Inst, Dept Mol Plant Physiol & Biophys, D-97070 Wurzburg, Germany
Pastor-Anglada, M:
Univ Barcelona IBUB, Inst Biomed, Dept Bioquim & Biol Mol, Barcelona, Spain
Natl Biomed Res Inst Liver & Gastrointestinal Dis, Barcelona, Spain
Bronze, Green Published
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