Combination therapy for autoimmune diseases: the rheumatoid arthritis model

Fathy, Nevine; Fürst, Daniel E.

doi:10.1007/978-3-662-04759-0_2

Cited by 2 publications

(2 citation statements)

References 68 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…CQ itself is a weak antirheumatic drug, but it is attractive in combination treatment because of its modest toxicity pattern (11). In RA treatment, CQ or hydroxychloroquine (HCQ) is often successfully combined with the anchor drug MTX as well as with other drugs (12,13).…”

mentioning

confidence: 99%

Acquired resistance to chloroquine in human CEM T cells is mediated by multidrug resistance–associated protein 1 and provokes high levels of cross‐resistance to glucocorticoids

Oerlemans

Heijden

Vink

et al. 2006

Arthritis & Rheumatism

View full text Add to dashboard Cite

Objective. To explore the onset and molecular mechanism of resistance to the antimalarial diseasemodifying antirheumatic drug (DMARD) chloroquine (CQ) in human CEM T cells.Methods. Human CEM cells were used as an in vitro model system to study the development of CQ resistance by growing cells in stepwise increasing concentrations of CQ.Results. Over a period of 6 months, CEM cell lines developed 4-5-fold resistance to CQ. CQ resistance was associated with the specific overexpression of multidrug resistance-associated protein 1 (MRP-1), an ATP-driven drug efflux pump. This was illustrated by 1) overexpression of MRP-1 by Western blotting and 2) the complete reversal of CQ resistance by the MRP-1 transport inhibitors MK571 and probenecid. Importantly, CQ-resistant CEM cells retained full sensitivity to other DMARDs, including methotrexate, leflunomide, cyclosporin A, and sulfasalazine, but exhibited a high level of cross-resistance (>1,000-fold) to the glucocorticoid dexamethasone. The mechanistic basis for the latter was associated with aberrant signaling via the cAMP-protein kinase A pathway, since the cAMP-inducing agent forskolin reversed dexamethasone resistance. Finally, CQ-resistant CEM cells displayed a markedly reduced capacity to release proinflammatory cytokines (tumor necrosis factor ␣) and chemokines (interleukin-8).Conclusion. Induction of overexpression of the multidrug resistance efflux transporter MRP-1 can emerge after long-term exposure to CQ and results in CQ resistance and collateral resistance to dexamethasone. These findings warrant further detailed investigations into the possible role of MRP-1 and other members of the superfamily of drug efflux pumps in diminishing the efficacy of DMARDs in rheumatoid arthritis treatment.

show abstract

mentioning

confidence: 99%

Acquired resistance to chloroquine in human CEM T cells is mediated by multidrug resistance–associated protein 1 and provokes high levels of cross‐resistance to glucocorticoids

Oerlemans

Heijden

Vink

et al. 2006

Arthritis & Rheumatism

View full text Add to dashboard Cite

show abstract

“…The antimalarial DMARD (hydroxy)chloroquine has relatively little activity as a single agent, but is used in combinations with other DMARDs (6,104,105). Chloroquine has been identified as a substrate, as well as an inhibitor of Pgp and MRP1 (106 -108).…”

Section: (Hydroxy)chloroquinementioning

confidence: 99%

Multidrug resistance proteins in rheumatoid arthritis, role in disease‐modifying antirheumatic drug efficacy and inflammatory processes: an overview

Jansen¹,

Scheper

Dijkmans

2003

Scandinavian Journal of Rheumatology

View full text Add to dashboard Cite

Drug resistance is generally accepted as an important cause of treatment failure for patients with neoplastic or infectious diseases. Molecular mechanisms underlying drug resistance include the action of drug efflux pumps belonging to the super-family of ATP binding cassette (ABC) proteins, which mediate the cellular extrusion of a large variety of therapeutic drugs, a phenotype that is referred to as multidrug resistance (MDR). Unlike neoplastic and infectious diseases, chronic inflammatory diseases have received little attention. The potential role of ABC transporters in determining the efficacy of anti-rheumatic drugs, notably disease modifying anti-rheumatic drugs (DMARDs), in patients with rheumatoid arthritis is unclear. Based on knowledge from the field of oncology and immunology, this review concentrates on the pharmacological role of MDR proteins in the (clinical) efficacy of several DMARDs, as well as the physiological role of MDR proteins in transporting signalling molecules important in inflammatory processes.

show abstract

Combination therapy for autoimmune diseases: the rheumatoid arthritis model

Cited by 2 publications

References 68 publications

Acquired resistance to chloroquine in human CEM T cells is mediated by multidrug resistance–associated protein 1 and provokes high levels of cross‐resistance to glucocorticoids

Acquired resistance to chloroquine in human CEM T cells is mediated by multidrug resistance–associated protein 1 and provokes high levels of cross‐resistance to glucocorticoids

Multidrug resistance proteins in rheumatoid arthritis, role in disease‐modifying antirheumatic drug efficacy and inflammatory processes: an overview

Contact Info

Product

Resources

About