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

C. Arimany-Nardi; E. Errasti-Murugarren; G. Minuesa; J. Martinez-Picado; V. Gorboulev; H. Koepsell; M. Pastor-Anglada

doi:10.1111/bph.12748

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

C. Arimany-Nardi, E. Errasti-Murugarren, G. Minuesa, J. Martinez-Picado, V. Gorboulev, H. Koepsell, M. Pastor-Anglada

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Inhibidors d'ADN metiltransferases (DNMT), com ara azacitidina, decitabina i zebularina, s'utilitzen per al tractament epigenètic del càncer. La seva acció pot dependre de la translocació a través de la membrana plasmàtica. L'objectiu d'aquest estudi va ser identificar les proteïnes transportadores que contribueixen a l'acció inhibidora de DNMT. Enfocament experimental Les interaccions farmacològiques amb proteïnes hCNT i hENT seleccionades es van estudiar en cèl·lules HeLa transfectades transitòriament i oòcits Xenopus laevis. Resultats clau La captació de zebularina va ser intervinguda per hCNT1, hCNT3 i hENT2. Decitabina interaccionava amb però no era translocada per qualsevol tipus de transportador nucleòsid (NT). L'expressió de hCNT en el domini apical de les cèl·lules MDCK promou un flux net vectorial de zebularina. Ni hOCT1 ni hOCT2 transportaven decitabina, però ambdues estaven implicades en l'eflux de zebularina, suggerint que aquestes proteïnes actuen com a transportadors d'eflux. Les variants polimòrfiques de hOCT1, conegudes per alterar la funció, van disminuir l'eflux de zebularina. Conclusions i implicacions Aquest estudi destaca la influència dels NT humans i els hOCT en la farmacocinètica i la farmacodinàmica d'inhibidors DNMT seleccionats. Com que els hOCT també poden comportar-se com a transportadors d'eflux, podrien contribuir tant a la quimioresistència com a la quimio sensibilitat, depenent de la naturalesa del fàrmac o combinació de fàrmacs utilitzats en el tractament del càncer. © 2014 The British Pharmacological Society.

Idioma original	Anglès
Pàgines (de-a)	3868-3880
Revista	British Journal of Pharmacology
Volum	171
Número	16
DOIs	https://doi.org/10.1111/bph.12748
Estat de la publicació	Publicada - 1 de gen. 2014

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10.1111/bph.12748

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https://www.scopus.com/pages/publications/84905011551

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@article{e8d6348d8f9043c8bf78a180e8f50e66,

title = "Nucleoside transporters and human organic cation transporter 1 determine the cellular handling of DNA-methyltransferase inhibitors",

abstract = "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. {\textcopyright} 2014 The British Pharmacological Society.",

author = "C. Arimany-Nardi and E. Errasti-Murugarren and G. Minuesa and J. Martinez-Picado and V. Gorboulev and H. Koepsell and M. Pastor-Anglada",

year = "2014",

month = jan,

day = "1",

doi = "10.1111/bph.12748",

language = "English",

volume = "171",

pages = "3868--3880",

journal = "British Journal of Pharmacology",

issn = "0007-1188",

publisher = "John Wiley and Sons Inc.",

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}

Nucleoside transporters and human organic cation transporter 1 determine the cellular handling of DNA-methyltransferase inhibitors. / Arimany-Nardi, C.; Errasti-Murugarren, E.; Minuesa, G. et al.
In: British Journal of Pharmacology, Vol. 171, Núm. 16, 01.01.2014, pàg. 3868-3880.

Producció científica: Contribució a revista › Article › Recerca › Avaluat per experts

TY - JOUR

T1 - Nucleoside transporters and human organic cation transporter 1 determine the cellular handling of DNA-methyltransferase inhibitors

AU - Arimany-Nardi, C.

AU - Errasti-Murugarren, E.

AU - Minuesa, G.

AU - Martinez-Picado, J.

AU - Gorboulev, V.

AU - Koepsell, H.

AU - Pastor-Anglada, M.

PY - 2014/1/1

Y1 - 2014/1/1

N2 - 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. © 2014 The British Pharmacological Society.

AB - 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. © 2014 The British Pharmacological Society.

UR - https://www.scopus.com/pages/publications/84905011551

U2 - 10.1111/bph.12748

DO - 10.1111/bph.12748

M3 - Article

SN - 0007-1188

VL - 171

SP - 3868

EP - 3880

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

IS - 16

ER -

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

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