Glucocorticoids (GCs) are commonly used in the treatment of (chronic) inflammatory diseases and cancer, but inherent or acquired resistance to these drugs limits their optimal efficacy. The availability of drugs that could modulate GC resistance is therefore of potential clinical interest.
To explore the molecular basis of GC sensitisation of GC resistant monocytic/macrophage cells after chronic exposure to sulfasalazine.
Human monocytic/macrophage THP1 and U937 cells represent a cell line model system characterised by inherent resistance to the GCs dexamethasone and prednisolone. Both cell lines were chronically exposed in vitro to 0.3-0.6 mM sulfasalazine (SSZ) for approximately 3 months, after which they were characterised for GC sensitivity, expression levels of GC receptor and components of the nuclear factor kappa B (NFkappaB) signalling pathway, and their ability to undergo GC induced apoptosis.
Chronic exposure to SSZ markedly sensitised both U937 and THP1 cells to dexamethasone (781-fold and 1389-fold, respectively) and prednisolone (562-fold and 1220-fold, respectively). Restoration of GC sensitivity in cells exposed to SSZ was provoked via GC induced apoptosis, coinciding with inhibition of NFkappaB activation. Moreover, western blot analysis revealed a markedly increased expression of glucocorticoid receptor alpha (GRalpha) in cells exposed to SSZ. Since GRalpha mRNA levels were only marginally increased, these results suggest that an altered post-transcriptional mechanism was operable which conferred a stable GRalpha protein on SSZ exposed cells.
These results suggest that chronic targeting of the NFkappaB signalling pathway by SSZ may be exploited as a novel strategy to stabilise GRalpha expression and thereby sensitise primary resistant cells to GCs.