Glucocorticoid receptor modulators in inflammation and oncology

Glucocorticoid hormones produce a diverse array of immunological and metabolic effects. Their antiinflammatory properties are commonly utilized in the treatment of inflammatory diseases and cancer, but they often cause severe side effects. In recent years, we have gained a greater understanding of the hormone, together with the ubiquitously expressed glucocorticoid receptor (GR) and downstream effector pathways. This hydrophobic hormone diffuses across the plasma membrane to gain access to the cytoplasmic GR. The activated GR subsequently translocates to the nucleus to modulate target gene and transcription factor activity. It is now clear that the GR is responsible for modulating target genes in a number of discrete and dissociable ways. This has allowed selective targeting of particular subsets of genes by mutated GRs, and by novel, synthetic ligands, in a manner analogous to the selective estrogen receptor modulators (SERMs) used in breast cancer treatment. It is clear that the antiinflammatory effects of glucocorticoids are mediated by binding to and interference with the function of other transcription factors, notably NF-κB, also an important factor in cell survival signaling. A concerted effort is now under way to find selective GR modulators that retain these beneficial properties while showing an improved side effect profile. Copyright 2008 Prous Science, S.A.U. or its licensors. All rights reserved.