Transport Mechanisms and Their Pathology-induced Regulation Govern Tyrosine Kinase Inhibitor Delivery in Rheumatoid Arthritis

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2013 Jan 4

PMID 23284953

Citations 13

Authors

Christian Schmidt-Lauber

Saliha Harrach

Thomas Pap

Meike Fischer

Marion Victor

Marianne Heitzmann

Uwe Hansen

Manfred Fobker

Stefan-Martin Brand

Aleksandra Sindic

Hermann Pavenstadt

Bayram Edemir

Eberhard Schlatter

Jessica Bertrand

Giuliano Ciarimboli

Affiliations

Soon will be listed here.

Abstract

Background: Tyrosine kinase inhibitors (TKIs) are effective in treating malignant disorders and were lately suggested to have an impact on non-malignant diseases. However, in some inflammatory conditions like rheumatoid arthritis (RA) the in vivo effect seemed to be moderate. As most TKIs are taken up actively into cells by cell membrane transporters, this study aimed to evaluate the role of such transporters for the accumulation of the TKI Imatinib mesylates in RA synovial fibroblasts as well as their regulation under inflammatory conditions.

Methodology/principal Findings: The transport and accumulation of Imatinib was investigated in transporter-transfected HEK293 cells and human RA synovial fibroblasts (hRASF). Transporter expression was quantified by qRT-PCR. In transfection experiments, hMATE1 showed the highest apparent affinity for Imatinib among all known Imatinib transporters. Experiments quantifying the Imatinib uptake in the presence of specific transporter inhibitors and after siRNA knockdown of hMATE1 indeed identified hMATE1 to mediate Imatinib transport in hRASF. The anti-proliferative effect of Imatinib on PDGF stimulated hRASF was quantified by cell counting and directly correlated with the uptake activity of hMATE1. Expression of hMATE1 was investigated by Western blot and immuno-fluorescence. Imatinib transport under disease-relevant conditions, such as an altered pH and following stimulation with different cytokines, was also investigated by HPLC. The uptake was significantly reduced by an acidic extracellular pH as well as by the cytokines TNFα, IL-1β and IL-6, which all decreased the expression of hMATE1-mRNA and protein.

Conclusion/significance: The regulation of Imatinib uptake via hMATE1 in hRASF and resulting effects on their proliferation may explain moderate in vivo effects on RA. Moreover, our results suggest that investigating transporter mediated drug processing under normal and pathological conditions is important for developing intracellular acting drugs used in inflammatory diseases.

Citing Articles

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Thioacetamide-Induced Acute Liver Injury Increases Metformin Plasma Exposure by Downregulating Renal OCT2 and MATE1 Expression and Function.

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References

Widmer N, Beguin A, Rochat B, Buclin T, Kovacsovics T, Duchosal M . Determination of imatinib (Gleevec) in human plasma by solid-phase extraction-liquid chromatography-ultraviolet absorbance detection. J Chromatogr B Analyt Technol Biomed Life Sci. 2004; 803(2):285-92. DOI: 10.1016/j.jchromb.2004.01.006. View

McInnes I, Schett G . Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol. 2007; 7(6):429-42. DOI: 10.1038/nri2094. View

Bach M, Grigat S, Pawlik B, Fork C, Utermohlen O, Pal S . Fast set-up of doxycycline-inducible protein expression in human cell lines with a single plasmid based on Epstein-Barr virus replication and the simple tetracycline repressor. FEBS J. 2007; 274(3):783-90. DOI: 10.1111/j.1742-4658.2006.05623.x. View

Grimminger F, Schermuly R, Ghofrani H . Targeting non-malignant disorders with tyrosine kinase inhibitors. Nat Rev Drug Discov. 2010; 9(12):956-70. DOI: 10.1038/nrd3297. View

Akashi N, Matsumoto I, Tanaka Y, Inoue A, Yamamoto K, Umeda N . Comparative suppressive effects of tyrosine kinase inhibitors imatinib and nilotinib in models of autoimmune arthritis. Mod Rheumatol. 2010; 21(3):267-75. DOI: 10.1007/s10165-010-0392-5. View

Gronowicz G, Hadjimichael J, Richards D, Cerami A, Rossomando E . Correlation between tumor necrosis factor-alpha (TNF-alpha)-induced cytoskeletal changes and human collagenase gene induction. J Periodontal Res. 1992; 27(6):562-8. DOI: 10.1111/j.1600-0765.1992.tb01737.x. View

Distler J, Distler O . Tyrosine kinase inhibitors for the treatment of fibrotic diseases such as systemic sclerosis: towards molecular targeted therapies. Ann Rheum Dis. 2009; 69 Suppl 1:i48-51. DOI: 10.1136/ard.2009.120196. View

Kameda H, Ishigami H, Suzuki M, Abe T, Takeuchi T . Imatinib mesylate inhibits proliferation of rheumatoid synovial fibroblast-like cells and phosphorylation of Gab adapter proteins activated by platelet-derived growth factor. Clin Exp Immunol. 2006; 144(2):335-41. PMC: 1809657. DOI: 10.1111/j.1365-2249.2006.03067.x. View

Rosenbloom J, Castro S, Jimenez S . Narrative review: fibrotic diseases: cellular and molecular mechanisms and novel therapies. Ann Intern Med. 2010; 152(3):159-66. DOI: 10.7326/0003-4819-152-3-201002020-00007. View

10.

Wang L, Giannoudis A, Lane S, Williamson P, Pirmohamed M, Clark R . Expression of the uptake drug transporter hOCT1 is an important clinical determinant of the response to imatinib in chronic myeloid leukemia. Clin Pharmacol Ther. 2007; 83(2):258-64. DOI: 10.1038/sj.clpt.6100268. View

11.

Grigat S, Fork C, Bach M, Golz S, Geerts A, Schomig E . The carnitine transporter SLC22A5 is not a general drug transporter, but it efficiently translocates mildronate. Drug Metab Dispos. 2008; 37(2):330-7. DOI: 10.1124/dmd.108.023929. View

12.

Kido Y, Matsson P, Giacomini K . Profiling of a prescription drug library for potential renal drug-drug interactions mediated by the organic cation transporter 2. J Med Chem. 2011; 54(13):4548-58. PMC: 3257218. DOI: 10.1021/jm2001629. View

13.

Thomas J, Wang L, Clark R, Pirmohamed M . Active transport of imatinib into and out of cells: implications for drug resistance. Blood. 2004; 104(12):3739-45. DOI: 10.1182/blood-2003-12-4276. View

14.

Grundemann D, Harlfinger S, Golz S, Geerts A, Lazar A, Berkels R . Discovery of the ergothioneine transporter. Proc Natl Acad Sci U S A. 2005; 102(14):5256-61. PMC: 555966. DOI: 10.1073/pnas.0408624102. View

15.

Rosengren S, Corr M, Boyle D . Platelet-derived growth factor and transforming growth factor beta synergistically potentiate inflammatory mediator synthesis by fibroblast-like synoviocytes. Arthritis Res Ther. 2010; 12(2):R65. PMC: 2888219. DOI: 10.1186/ar2981. View

16.

Ciarimboli G, Struwe K, Arndt P, Gorboulev V, Koepsell H, Schlatter E . Regulation of the human organic cation transporter hOCT1. J Cell Physiol. 2004; 201(3):420-8. DOI: 10.1002/jcp.20081. View

17.

Wilde S, Schlatter E, Koepsell H, Edemir B, Reuter S, Pavenstadt H . Calmodulin-associated post-translational regulation of rat organic cation transporter 2 in the kidney is gender dependent. Cell Mol Life Sci. 2009; 66(10):1729-40. PMC: 11115569. DOI: 10.1007/s00018-009-9145-z. View

18.

Paniagua R, Robinson W . Imatinib for the treatment of rheumatic diseases. Nat Clin Pract Rheumatol. 2007; 3(4):190-1. DOI: 10.1038/ncprheum0465. View

19.

Ito S, Kusuhara H, Kuroiwa Y, Wu C, Moriyama Y, Inoue K . Potent and specific inhibition of mMate1-mediated efflux of type I organic cations in the liver and kidney by pyrimethamine. J Pharmacol Exp Ther. 2010; 333(1):341-50. DOI: 10.1124/jpet.109.163642. View

20.

Minematsu T, Giacomini K . Interactions of tyrosine kinase inhibitors with organic cation transporters and multidrug and toxic compound extrusion proteins. Mol Cancer Ther. 2011; 10(3):531-9. PMC: 3063525. DOI: 10.1158/1535-7163.MCT-10-0731. View