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. 2004 Feb;63(2):138–143. doi: 10.1136/ard.2002.005249

Development of sulfasalazine resistance in human T cells induces expression of the multidrug resistance transporter ABCG2 (BCRP) and augmented production of TNFα

J van der Heijden 1, M C de Jong 1, B Dijkmans 1, W Lems 1, R Oerlemans 1, I Kathmann 1, C Schalkwijk 1, G Scheffer 1, R Scheper 1, G Jansen 1
PMCID: PMC1754889  PMID: 14722201

Abstract

Objective: To determine whether overexpression of cell membrane associated drug efflux pumps belonging to the family of ATP binding cassette (ABC) proteins contributes to a diminished efficacy of sulfasalazine (SSZ) after prolonged cellular exposure to this disease modifying antirheumatic drug (DMARD).

Methods: A model system of human T cells (CEM) was used to expose cells in vitro to increasing concentrations of SSZ for a period of six months. Cells were then characterised for the expression of drug efflux pumps: P-glycoprotein (Pgp, ABCB1), multidrug resistance protein 1 (MRP1, ABCC1), and breast cancer resistance protein (BCRP, ABCG2).

Results: Prolonged exposure of CEM cells to SSZ provoked resistance to SSZ as manifested by a 6.4-fold diminished antiproliferative effect of SSZ compared with parental CEM cells. CEM cells resistant to SSZ (CEM/SSZ) showed a marked induction of ABCG2/BCRP, Pgp expression was not detectable, while MRP1 expression was even down regulated. A functional role of ABCG2 in SSZ resistance was demonstrated by 60% reversal of SSZ resistance by the ABCG2 blocker Ko143. Release of the proinflammatory cytokine tumour necrosis factor α (TNFα) was threefold higher in CEM/SSZ cells than in CEM cells. Moreover, twofold higher concentrations of SSZ were required to inhibit TNFα release from CEM/SSZ cells compared with CEM cells.

Conclusion: Collectively, ABCG2 induction, augmented TNFα release, and less efficient inhibition of TNFα production by SSZ may contribute to diminished efficacy after prolonged exposure to SSZ. These results warrant further clinical studies to verify whether drug efflux pumps, originally identified for their roles in cytostatic drug resistance, can also be induced by SSZ or other DMARDs.

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Figure 1 .

Figure 1

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(A) Onset of SSZ resistance in human CEM (T) cells. SSZ resistance was provoked by culturing CEM (T) cells in stepwise increasing concentrations SSZ over time. (B) SSZ sensitivity for CEM (T) cells, CEM/SSZ1.5, and CEM/SSZ2.5 cells. Antiproliferative effects were assessed after 72 hours' exposure to SSZ. Results are the mean of 3–5 separate experiments (SD <20%).

Figure 2 .

Figure 2

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(A) Expression of MDR transporters Pgp, MRP1, and ABCG2/BCRP in CEM (T) and CEM/SSZ1.5 cells. Western blots were performed using total cell lysates of CEM (T) and CEM/SSZ1.5 cells. Cell lysates of CEM/VBL100,64 2008/MRP1,32 and MCF7/MR40 served as positive control for Pgp, MRP1, and ABCG2, respectively. For CEM (T) and CEM/SSZ1.5 cells, 50 µg of cell lysate was applied on the sodium dodecyl sulphate-polyacrylamide gel, and for the controls 10 µg protein. Pgp was detected by the monoclonal antibody JSB1, MRP1 was detected by the monoclonal antibody MRPr1, and ABCG2 was detected by the monoclonal antibody BXP21.32,33 (B) Reversal of SSZ resistance in CEM/SSZ1.5 cells by ABCG2 blocker Ko143, but not by Pgp blocker verapamil or MRP1 blocker MK571. CEM/SSZ1.5 cells were incubated in medium containing non-toxic concentrations of the ABCG2 blocker Ko143 (0.5 µM), MRP1 blocker MK571 (20 µM), or Pgp blocker verapamil (10 µM) and evaluated for SSZ sensitivity compared with parental CEM (T) cells as described in fig 1B. Results are presented as the mean of three experiments (SD <20%).

Figure 3 .

Figure 3

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(A) TNFα production by CEM (T), CEM/SSZ1.5, and CEM/SSZ2.5 cells (3x105/ml) after 24 hours' stimulation with PMA/ionomycin in the absence or presence of a concentration range of SSZ. TNFα levels were determined by ELISA. Results are mean (SD) of 5–7 separate experiments. (B) NFkB p65 expression in nuclear extracts of CEM (T) cells and CEM/SSZ1.5 cells after 24 hours' stimulation with PMA/ionomycin in the absence or presence of SSZ (1.0 mM).

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