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.
Highlights
Rheumatic diseases such as rheumatoid arthritis (RA) are chronic and debilitating inflammatory diseases, for which there is currently no cure, and which require long-term symptomatic treatment
The saracatinib uptake observed in control HEK293 cells is probably due to the low endogenous expression of transporters (OCT1-3 and OCTN1), which are able to mediate the transport of saracatinib (Supplementary Fig. 2)
The tyrosine kinases (TKs) inhibitors (TKIs) saracatinib is a potent dual inhibitor of c-Src and c-Abl kinases, which are involved in cell proliferation, differentiation, and survival[22, 27]
Summary
Rheumatic diseases such as rheumatoid arthritis (RA) are chronic and debilitating inflammatory diseases, for which there is currently no cure, and which require long-term symptomatic treatment. There is a strong interest in TK inhibitors (TKIs) as “small molecules” for RA therapy[6, 8] Such “small molecules” have a comparable risk versus benefit profile of currently available biologic agents combined with the advantage of low costs[9] and of oral administration, which is of pivotal importance in determining patients’ compliance and treatment success[4]. TK dependent pathways activated in RA include the Janus kinases/signal transducers and activators of transcription (JAK/STAT) pathway, spleen tyrosine kinase (Syk), c-Src, focal adhesion kinase (FAK), and c-Abl signaling[6]. In this context, the TKI saracatinib is of special interest, because it acts as a dual kinase inhibitor, with selective actions as c-Src- and c-Abl-TKI10. Both PDGFR and its ligands are overexpressed in RA synovial tissue, and PDGF is a potent stimulant of synovial hyperplasia in RA17
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