Importance of the novel organic cation transporter 1 for tyrosine kinase inhibition by saracatinib in rheumatoid arthritis synovial fibroblasts
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Importance of the novel organic cation transporter 1 for tyrosine kinase inhibition by saracatinib in rheumatoid arthritis synovial fibroblasts. / Harrach, Saliha; Edemir, Bayram; Schmidt-Lauber, Christian; Pap, Thomas; Bertrand, Jessica; Ciarimboli, Giuliano.
In: SCI REP-UK, Vol. 7, No. 1, 28.04.2017, p. 1258.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Importance of the novel organic cation transporter 1 for tyrosine kinase inhibition by saracatinib in rheumatoid arthritis synovial fibroblasts
AU - Harrach, Saliha
AU - Edemir, Bayram
AU - Schmidt-Lauber, Christian
AU - Pap, Thomas
AU - Bertrand, Jessica
AU - Ciarimboli, Giuliano
PY - 2017/4/28
Y1 - 2017/4/28
N2 - 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.
AB - 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.
KW - Arthritis, Rheumatoid/pathology
KW - Benzodioxoles/metabolism
KW - Cell Proliferation/drug effects
KW - Cells, Cultured
KW - Enzyme Inhibitors/metabolism
KW - Fibroblasts/drug effects
KW - Humans
KW - Organic Cation Transport Proteins/metabolism
KW - Protein-Tyrosine Kinases/antagonists & inhibitors
KW - Quinazolines/metabolism
KW - Symporters
U2 - 10.1038/s41598-017-01438-4
DO - 10.1038/s41598-017-01438-4
M3 - SCORING: Journal article
C2 - 28455521
VL - 7
SP - 1258
JO - SCI REP-UK
JF - SCI REP-UK
SN - 2045-2322
IS - 1
ER -