Involvement of breast cancer resistance protein expression on rheumatoid arthritis synovial tissue macrophages in resistance to methotrexate and leflunomide

Abstract

Objective. To determine whether multidrugresistance efflux transporters are expressed on immune effector cells in synovial tissue from patients with rheumatoid arthritis (RA) and compromise the efficacy of methotrexate (MTX) and leflunomide (LEF).Methods. Synovial tissue biopsy samples obtained from RA patients before treatment and 4 months after starting treatment with MTX (n ‫؍‬ 17) or LEF (n ‫؍‬ 13) were examined by immunohistochemical staining and digital image analysis for the expression of the drug efflux transporters P-glycoprotein, multidrug resistance-associated protein 1 (MRP-1) through MRP-5, MRP-8, MRP-9, and breast cancer resistance protein (BCRP), and the relationship to clinical efficacy of MTX and LEF was assessed.Results. BCRP expression was observed in all RA synovial biopsy samples, both pretreatment and posttreatment, but not in control noninflammatory synovial tissue samples from orthopedic patients. BCRP expression was found both in the intimal lining layer and on macrophages and endothelial cells in the synovial sublining. Total numbers of macrophages in RA patients decreased upon treatment; in biopsy samples with persistently high macrophage counts, 2-fold higher BCRP expression was observed. Furthermore, median BCRP expression was significantly increased (3-fold) in nonresponders to disease-modifying antirheumatic drugs (DMARDs) compared with responders to DMARDs (P ‫؍‬ 0.048). Low expression of MRP-1 was found on synovial macrophages, along with moderate expression in T cell areas of synovial biopsy specimens from one-third of the RA patients.Conclusion. These findings show that the drug resistance-related proteins BCRP and MRP-1 are expressed on inflammatory cells in RA synovial tissue. Since MTX is a substrate for both BCRP and MRP-1, and LEF is a high-affinity substrate for BCRP, these transporters may contribute to reduced therapeutic efficacy of these DMARDs.

Treatment strategy based on targeting P-glycoprotein on peripheral lymphocytes in patients with systemic autoimmune disease

“…P-gp, a 170-kDa product of the MDR-1 gene, is a member of the adenosine triphosphate (ATP)-binding cassette (ABC) transporter superfamily of genes and functions as an energy-dependent transmembrane efflux pump. Overexpression of P-gp results in reduction of intracellular concentrations of xenobiotics, drugs and poisons, such as vinca alkaloids, anthracyclines, antimalarials, colchicines, cyclosporine, and glucocorticoids (Table 1) [8][9][10][11][12][13]. Thus, P-gp appears to be a double-edged sword, involved in both the protection of cells from these drugs and the development of resistance to them.…”

“…Such a secondary failure is often experienced in patients who are maintained Fig. 1 Up-regulation of P-glycoprotein expression on lymphocytes by various stimuli [13,14]. a MDR-1 mRNA expression was examined by reverse transcriptasepolymerase chain reaction using total RNA extracted from peripheral blood mononuclear cells (PBMCs) incubated with 10 ng/ml of IL-2 or 50 lg/ml of 6.9 kDa fragmented hyaluronan (Fr.…”

“Target-Site” Drug Metabolism and Transport

“…For example, the expression of P-gp on proinflammatory Th17 cells is a determining factor in the resistance of these cells to glucocorticoid treatment in autoimmune diseases (Ramesh et al, 2014). In vitro results suggest that MRP1 and BCRP expression in synovial tissue of rheumatic patients may impact the clinical efficacy of diseasemodifying antirheumatic drugs such as methotrexate and leflunomide (van der Heijden et al, 2009). Finally, some patients taking pravastatin and gemfibrozil in combination experienced increased pravastatin plasma levels and decreased renal clearance (altered pharmacokinetics) resulting in increased pravastatin-associated adverse events, and preliminary evidence suggests this drug-drug interaction may involve inhibition of human organic anion transporter 3 (hOAT3)-mediated pravastatin transport by gemfibrozil (Kyrklund et al, 2003;NakagomiHagihara et al, 2007).…”

Genetic Polymorphisms in Low-Dose Methotrexate Transporters: Current Relevance as Methotrexate Therapeutic Outcome Biomarkers

“…It is a polytopic membrane protein present in basolateral plasma membranes in all intestinal regions and consists of 17 trans membrane regions [36,73]. It was reported as being expressed on CD3 + T cells in lymphocytic aggregates and to a lesser extent in RA synovial tissue macrophages in the intimal lining layer and the synovial sublining, and on endothelial cells [77]. Moreover, it has been described as a transporter of a number of different drugs including MTX [78].…”