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. 2004 Feb;63(2):131–137. doi: 10.1136/ard.2003.006494

Acquired resistance of human T cells to sulfasalazine: stability of the resistant phenotype and sensitivity to non-related DMARDs

J van der Heijden 1, M C de Jong 1, B Dijkmans 1, W Lems 1, R Oerlemans 1, I Kathmann 1, G Scheffer 1, R Scheper 1, Y Assaraf 1, G Jansen 1
PMCID: PMC1754886  PMID: 14722200

Abstract

Background: A recent study from our laboratory showed that induction of the multidrug resistance related drug efflux pump ABCG2 contributed to acquired resistance of human T cells to the disease modifying antirheumatic drug (DMARD) sulfasalazine (SSZ).

Objectives: To investigate the duration of SSZ resistance and ABCG2 expression after withdrawal of SSZ and rechallenging with SSZ, and to assess the impact of SSZ resistance on responsiveness to other DMARDs.

Methods: Human CEM cells (T cell origin) with acquired resistance to SSZ (CEM/SSZ) were characterised for (a) SSZ sensitivity and ABCG2 expression during withdrawal and rechallenge of SSZ, and (b) antiproliferative efficacy of other DMARDs.

Results: ABCG2 protein expression was stable for at least 4 weeks when CEM/SSZ cells were grown in the absence of SSZ, but gradually declined, along with SSZ resistance levels, to non-detectable levels after withdrawal of SSZ for 6 months. Rechallenging with SSZ led to a rapid (<2.5 weeks) resumption of SSZ resistance and ABCG2 expression as in the original CEM/SSZ cells. CEM/SSZ cells displayed diminished sensitivity to the DMARDs leflunomide (5.1-fold) and methotrexate (1.8-fold), were moderately more sensitive (1.6–2.0 fold) to cyclosporin A and chloroquine, and markedly more sensitive (13-fold) to the glucocorticoid dexamethasone as compared with parental CEM cells.

Conclusion: The drug efflux pump ABCG2 has a major role in conferring resistance to SSZ. The collateral sensitivity of SSZ resistant cells for some other (non-related) DMARDs may provide a further rationale for sequential mono- or combination therapies with distinct DMARDs upon decreased efficacy of SSZ.

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Figure 1 .

Figure 1

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(A) Time course of sensitivity to sulfasalazine (SSZ) of CEM (T) during development of SSZ resistance, after withdrawal of SSZ from CEM/SSZ1.5 cells and rechallenge of revertant CEM/SSZ1.5 cells with SSZ. Parental CEM (T) cells (point A) were exposed to a starting concentration of 0.4 mM SSZ that was gradually increased to 1.5 mM over a period of 6 months to yield SSZ resistant CEM/SSZ1.5 cells (point B). From this point on CEM/SSZ1.5 were grown in the absence of SSZ to finally yield revertant CEM/SSZ1.5 cells that displayed again parental CEM (T) cell sensitivity to SSZ (point C). When revertant cells were re-exposed to 1.5 mM SSZ for 2.5 weeks (point D), CEM/SSZ1.5 resumed their original resistance level as observed at point B. IC50 values were determined after 72 hours' exposure of cells to SSZ. (B) ABCG2/BCRP and ABCC1/MRP1 protein expression, and mitoxantrone sensitivity of CEM (T) cells and (revertant) CEM/SSZ1.5 cells isolated at the various time points A–D. Cell lysates of 2008/MRP132 and MCF7/MR43 served as positive controls for ABCC1/MRP1 and ABCG2/BCRP, respectively (not shown). For CEM (T) and CEM/SSZ1.5 cells, 50 µg of total cell lysate was applied on the sodium dodecyl sulphate polyacrylamide gel, and for the controls 10 µg protein. ABCC1/MRP1 was detected by the monoclonal antibody MRPr1, and ABCG2/BCRP was detected by the monoclonal antibody BXP21.32,33 ß-Actin was used as a control for equal protein loading.

Figure 2 .

Figure 2

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(A) Antiproliferative effect of SSZ against CEM/SSZ1.5 cells isolated at various times (0–10 weeks) after withdrawal of SSZ from CEM/SSZ1.5 cells from point B in fig 1A: 0 days (closed circles), 3 days (open triangles), 1 week (closed triangles), 4 weeks (open diamonds), 10 weeks (closed squares). Antiproliferative effects/growth inhibition for SSZ were evaluated after 72 hours' exposure to SSZ and compared with those for parental CEM (T) cells (open circles). (B) Expression of ABCG2/BCRP and ABCC1/MRP1 protein of CEM/SSZ1.5 cells during withdrawal of SSZ for up to 10 weeks as in fig 2A. Lane A: parental CEM (T) cells; lane B: CEM/SSZ1.5 cells before withdrawal of SSZ; lanes C–F: CEM/SSZ1.5 cells 3 days, 7 days, 4 weeks, and 10 weeks, respectively, after withdrawal of SSZ. Note: sample E for ABCC1/MRP1 was not tested. (C) Reversal of SSZ resistance in CEM/SSZ1.5 cells by the ABCG2/BCRP blocker Ko143 before and after 4 weeks' withdrawal of SSZ. Symbols: (open triangle) parental CEM (T) cells, (open circles) CEM/SSZ1.5 cells, (closed circles) CEM/SSZ cells + 0.5 µM Ko143, (open squares) CEM/SSZ1.5 cells after 4 weeks' withdrawal of SSZ, (closed squares) CEM/SSZ1.5 cells after 4 weeks withdrawal of SSZ + 0.5 µM SSZ. Antiproliferative effects of SSZ were evaluated after 72 hours' exposure to SSZ in the absence or presence of Ko143.

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