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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 TNF\u03b1) 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.<\/jats:p>","DOI":"10.1038\/s41598-017-01438-4","type":"journal-article","created":{"date-parts":[[2017,4,24]],"date-time":"2017-04-24T10:12:57Z","timestamp":1493028777000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Importance of the novel organic cation transporter 1 for tyrosine kinase inhibition by saracatinib in rheumatoid arthritis synovial fibroblasts"],"prefix":"10.1038","volume":"7","author":[{"given":"Saliha","family":"Harrach","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bayram","family":"Edemir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Schmidt-Lauber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Pap","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Bertrand","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuliano","family":"Ciarimboli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,4,28]]},"reference":[{"key":"1438_CR1","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1093\/rheumatology\/39.2.122","volume":"39","author":"DL Scott","year":"2000","unstructured":"Scott, D. 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