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.
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.
Authors: M V Tzvetkov; S V Vormfelde; D Balen; I Meineke; T Schmidt; D Sehrt; I Sabolić; H Koepsell; J Brockmöller Journal: Clin Pharmacol Ther Date: 2009-06-17 Impact factor: 6.875
Authors: Sílvia Rodríguez-Mulero; Ekaitz Errasti-Murugarren; José Ballarín; Antonio Felipe; Alain Doucet; F Javier Casado; Marçal Pastor-Anglada Journal: Kidney Int Date: 2005-08 Impact factor: 10.612
Authors: P Arndt; C Volk; V Gorboulev; T Budiman; C Popp; I Ulzheimer-Teuber; A Akhoundova; S Koppatz; E Bamberg; G Nagel; H Koepsell Journal: Am J Physiol Renal Physiol Date: 2001-09
Authors: V Gorboulev; J C Ulzheimer; A Akhoundova; I Ulzheimer-Teuber; U Karbach; S Quester; C Baumann; F Lang; A E Busch; H Koepsell Journal: DNA Cell Biol Date: 1997-07 Impact factor: 3.311
Authors: Siennah R Miller; Xiaohong Zhang; Raymond K Hau; Joseph L Jilek; Erin Q Jennings; James J Galligan; Daniel H Foil; Kimberley M Zorn; Sean Ekins; Stephen H Wright; Nathan J Cherrington Journal: Mol Pharmacol Date: 2020-12-01 Impact factor: 4.436