• Home
  • Search Results
  • Nucleoside transporters and human organic cation transporter 1 determine the cellular handling of DNA-methyltransferase inhibitors.

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

British journal of pharmacology (2014-05-02)
C Arimany-Nardi, E Errasti-Murugarren, G Minuesa, J Martinez-Picado, V Gorboulev, H Koepsell, M Pastor-Anglada
ABSTRACT

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. 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. 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. 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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
MOPS, ≥99.5% (titration)
Sigma-Aldrich
Calcium chloride solution, BioUltra, for molecular biology, ~1 M in H2O
Sigma-Aldrich
L-Glutamine, meets USP testing specifications, suitable for cell culture, 99.0-101.0%, from non-animal source
Sigma-Aldrich
L-Glutamine, ReagentPlus®, ≥99% (HPLC)
Sigma-Aldrich
5-Aza-2′-deoxycytidine, ≥97%
Sigma-Aldrich
Calcium chloride, meets USP testing specifications
Sigma-Aldrich
Calcium chloride, anhydrous, BioReagent, suitable for insect cell culture, suitable for plant cell culture, ≥96.0%
Sigma-Aldrich
Calcium chloride, anhydrous, powder, 99.99% trace metals basis
Sigma-Aldrich
Uridine, ≥99%
SAFC
L-Glutamine
Sigma-Aldrich
MOPS, BioPerformance Certified, suitable for cell culture, ≥99.5% (titration)
Sigma-Aldrich
Uridine, powder, BioReagent, suitable for cell culture
Sigma-Aldrich
MPP+ iodide, ≥98% (HPLC), powder
Sigma-Aldrich
Cytidine, BioReagent, suitable for cell culture, powder, ≥99%
Sigma-Aldrich
Cytidine, 99%
Sigma-Aldrich
Quinine, suitable for fluorescence, anhydrous, ≥98.0% (dried material, NT)
Sigma-Aldrich
MOPS, BioUltra, for molecular biology, ≥99.5% (T)
Sigma-Aldrich
Quinine, 90%
Sigma-Aldrich
Calcium chloride, AnhydroBeads, −10 mesh, ≥99.9% trace metals basis
Sigma-Aldrich
L-Glutamine, BioUltra, ≥99.5% (NT)
Sigma-Aldrich
L-Glutamine, γ-irradiated, BioXtra, suitable for cell culture
Sigma-Aldrich
Dipyridamole, ≥98% (HPLC)
Sigma-Aldrich
MOPS, BioXtra, ≥99.5% (titration)
Sigma-Aldrich
Uridine, BioUltra, ≥99%
Supelco
Calcium ion solution for ISE, 0.1 M Ca, analytical standard (for ion-selective electrodes)
Supelco
L-Glutamine, Pharmaceutical Secondary Standard; Certified Reference Material
Supelco
Quinine, certified reference material, TraceCERT®
Sigma-Aldrich
S-(4-Nitrobenzyl)-6-thioinosine, ≥98%, solid
SAFC
MOPS
Sigma-Aldrich
MOPS, anhydrous, free-flowing, Redi-Dri, ≥99.5%