Open AccessAcquired 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
Author(s) -
Oerlemans Ruud,
van der Heijden Joost,
Vink Josefien,
Dijkmans Ben A. C.,
Kaspers Gertjan J. L.,
Lems Willem F.,
Scheffer George L.,
Ifergan Ilan,
Scheper Rik J.,
Cloos Jacqueline,
Assaraf Yehuda G.,
Jansen Gerrit
Publication year - 2006
Publication title -
arthritis & rheumatism
Language(s) - English
Resource type - Journals
eISSN - 1529-0131
pISSN - 0004-3591
DOI - 10.1002/art.21569
Subject(s) - efflux , pharmacology , proinflammatory cytokine , drug resistance , multiple drug resistance , probenecid , multidrug resistance associated protein 2 , biology , medicine , immunology , atp binding cassette transporter , transporter , inflammation , biochemistry , microbiology and biotechnology , gene
Objective To explore the onset and molecular mechanism of resistance to the antimalarial disease‐modifying 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 α) 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.