Molecular mechanisms of resistance to disease modifying antirheumatic drugs (DMARDs)

Background

Drug resistance is a common cause of treatment failure in infectious and neoplastic diseases. Relatively little is known about the molecular mechanisms of resistance to DMARDs.

Objective

To obtain insight into the onset and molecular mechanism(s) of resistance to 2 DMARDs: 1) the antimmalarial chloroquine (CHQ) and 2) sulfasalazine (SSZ), an inhibitor of the activation of NF-κB.

Methods

Human CEM (T) cells were used as an in vitro model system of a target cell in rheumatoid arthritis (RA). Resistance to CHQ and SSZ was provoked by growing CEM (T) cells in stepwise increasing concentrations of either of these DMARDs.

Results

Over a period of 5 months, CEM (T) cells developed a level of 4-5-fold resistance to CHQ and SSZ. The molecular basis of CHQ resistance appeared to be due to a 5-fold overexpression of one of the ATP-Binding Cassette (ABC) drug efflux proteins; the multidrug resistance-associated protein 1 (MRP1). Consistently, blockers of MRP1 (MK571 and probenecid) reversed CHQ resistance in CEM/CHQ cells. The molecular basis of SSZ resistance appeared to be due to a marked overexpression of another ABC protein; the breast cancer resistance protein (BCRP). A blocker of BCRP reversed resistance for SSZ in CEM/SSZ cells by more than 50%. Beyond this, CEM/SSZ revealed a diminished basal level of expression of cytoplasmic phosphorylated IκB-α and nuclear NF-κB(p65).

Conclusions

Members of the ABC family of drug efflux pumps (i.e. MRP1 and BCRP) can confer resistance to DMARDs (CHQ and SSZ, respectively). This result warrants further investigations into the contribution of drug efflux pumps in treatment failure of RA patients with DMARDs.