Importance of the novel organic cation transporter 1 for tyrosine kinase inhibition by saracatinib in rheumatoid arthritis synovial fibroblasts

Abstract Recent therapeutic approaches of rheumatoid arthritis (RA) address the use of small molecules such as tyrosine kinase inhibitors (TKIs). However, the TKIs developed to date have important side effects and/or scarce efficacy in inflammatory diseases such as RA. Since intracellular effective...

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Autores principales:	Saliha Harrach, Bayram Edemir, Christian Schmidt-Lauber, Thomas Pap, Jessica Bertrand, Giuliano Ciarimboli
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/12465898ab2a41cb94a18b3654366d8b
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spelling	oai:doaj.org-article:12465898ab2a41cb94a18b3654366d8b2021-12-02T15:04:53ZImportance of the novel organic cation transporter 1 for tyrosine kinase inhibition by saracatinib in rheumatoid arthritis synovial fibroblasts10.1038/s41598-017-01438-42045-2322https://doaj.org/article/12465898ab2a41cb94a18b3654366d8b2017-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-01438-4https://doaj.org/toc/2045-2322Abstract Recent therapeutic approaches of rheumatoid arthritis (RA) address the use of small molecules such as tyrosine kinase inhibitors (TKIs). However, the TKIs developed to date have important side effects and/or scarce efficacy in inflammatory diseases such as RA. Since intracellular effective TKIs must enter the cell to reach their intracellular targets, here we investigated the interaction of the TKI saracatinib, a dual inhibitor of c-Src and c-Abl signaling, with transporters for organic cations as well as the role of these transporters for the biological effect of saracatinib in human RA-synovial fibroblasts (hRASF). Saracatinib significantly reduced proliferation of hRASF. The cellular saracatinib uptake was mainly dependent on the human novel organic cation transporter 1 (hOCTN1), which showed the highest apparent affinity for saracatinib among all other transporters for organic cations analyzed here. In hRASF, saracatinib biologic function was dependent on hOCTN1. Further analysis showed that disease specific factors (pH, inflammatory cytokines such as TNFα) regulated saracatinib uptake in hRASF. The knowledge of which transporters mediate the specific uptake of TKIs in target cells and of how the expression and function of such transporters are regulated in RA is of highest priority to develop effective drugs for successful therapy with minimal side-effects.Saliha HarrachBayram EdemirChristian Schmidt-LauberThomas PapJessica BertrandGiuliano CiarimboliNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-9 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Saliha Harrach Bayram Edemir Christian Schmidt-Lauber Thomas Pap Jessica Bertrand Giuliano Ciarimboli Importance of the novel organic cation transporter 1 for tyrosine kinase inhibition by saracatinib in rheumatoid arthritis synovial fibroblasts
description	Abstract Recent therapeutic approaches of rheumatoid arthritis (RA) address the use of small molecules such as tyrosine kinase inhibitors (TKIs). However, the TKIs developed to date have important side effects and/or scarce efficacy in inflammatory diseases such as RA. Since intracellular effective TKIs must enter the cell to reach their intracellular targets, here we investigated the interaction of the TKI saracatinib, a dual inhibitor of c-Src and c-Abl signaling, with transporters for organic cations as well as the role of these transporters for the biological effect of saracatinib in human RA-synovial fibroblasts (hRASF). Saracatinib significantly reduced proliferation of hRASF. The cellular saracatinib uptake was mainly dependent on the human novel organic cation transporter 1 (hOCTN1), which showed the highest apparent affinity for saracatinib among all other transporters for organic cations analyzed here. In hRASF, saracatinib biologic function was dependent on hOCTN1. Further analysis showed that disease specific factors (pH, inflammatory cytokines such as TNFα) regulated saracatinib uptake in hRASF. The knowledge of which transporters mediate the specific uptake of TKIs in target cells and of how the expression and function of such transporters are regulated in RA is of highest priority to develop effective drugs for successful therapy with minimal side-effects.
format	article
author	Saliha Harrach Bayram Edemir Christian Schmidt-Lauber Thomas Pap Jessica Bertrand Giuliano Ciarimboli
author_facet	Saliha Harrach Bayram Edemir Christian Schmidt-Lauber Thomas Pap Jessica Bertrand Giuliano Ciarimboli
author_sort	Saliha Harrach
title	Importance of the novel organic cation transporter 1 for tyrosine kinase inhibition by saracatinib in rheumatoid arthritis synovial fibroblasts
title_short	Importance of the novel organic cation transporter 1 for tyrosine kinase inhibition by saracatinib in rheumatoid arthritis synovial fibroblasts
title_full	Importance of the novel organic cation transporter 1 for tyrosine kinase inhibition by saracatinib in rheumatoid arthritis synovial fibroblasts
title_fullStr	Importance of the novel organic cation transporter 1 for tyrosine kinase inhibition by saracatinib in rheumatoid arthritis synovial fibroblasts
title_full_unstemmed	Importance of the novel organic cation transporter 1 for tyrosine kinase inhibition by saracatinib in rheumatoid arthritis synovial fibroblasts
title_sort	importance of the novel organic cation transporter 1 for tyrosine kinase inhibition by saracatinib in rheumatoid arthritis synovial fibroblasts
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/12465898ab2a41cb94a18b3654366d8b
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Importance of the novel organic cation transporter 1 for tyrosine kinase inhibition by saracatinib in rheumatoid arthritis synovial fibroblasts

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