Comparison of two structurally diverse glucocorticoid receptor agonists: cortivazol selectively regulates a distinct set of genes separate from dexamethasone in CEM cells.

One goal of steroid research is precise differential regulation of gene expression by steroid hormone receptors through use of distinct ligands which modulate defined sets of cellular effects. Such "selective modulator" ligands are known for several receptors. Potent pyrazolo-glucocorticoid (11beta,16alpha)-21-(Acetyloxy)-11,17-dihydroxy-6,16-dimethyl-2'-phenyl-2'H-pregna-2,4,6-trieno[3,2-c]pyrazol-20-one) cortivazol activates the glucocorticoid receptor to regulate gene expression and can bring about apoptosis of leukemic CEM cells resistant to (9-fluoro-11,17-dihydroxy-17-(2-hydroxyacetyl)-10,13,16-trimethyl-6,7,8,11,12,14,15,16-octahydrocyclopenta[a]phenanthren-3-one) dexamethasone. We therefore tested the hypothesis that cortivazol and dexamethasone regulate non-identical sets of genes in CEM cells. We found that while cortivazol and dexamethasone overlap in regulation of most genes, each steroid regulates an exclusive set of transcripts in clone CEM-C7-14 (sensitive to apoptosis by both dexamethasone and cortivazol) and clone CEM-C1-15 (dexamethasone-resistant but cortivazol-sensitive). Fifty-seven genes were regulated uniquely to a statistically significant extent by cortivazol in both clones. Many of the cortivazol specific genes are key components of various signal transduction pathways. Our data clearly show cortivazol to be a selective modulator of GR action.