Dissociated glucocorticoid properties of 21-hidroxi-6, 19-epoxyprogesterone

ORQUEDA, ANDRES; PRESMAN, DIEGO; ALVAREZ, LAUTARO; KORDON, EDITH C; BURTON, GERARDO; PECCI, ADALI

Simposio; SISTAM 2010; 2010

Glucocorticoids (GCs) exert their action throughout two main mechanisms: transactivation (gene expression induction by GR binding to specific GRE sequences) and transrepression (modulation of different transcription factors activities). In clinical trials beneficial effects of GCs are often associated with transrepression, while adverse effects are associated with transactivation. 21-hidroxi-6,19-epoxyprogesterone (OP) is a GR ligand postulated as a putative steroid regulator glucocorticoid modulator (SRGM). Here, we investigated OP properties as a dissociated glucocorticoid. We found that OP behaves as an agonist in transrepression assays, as it inhibits Rel A and AP-1 activities as well as TNF-alfa mediated cox-2 and IL-8 induction. On an opposite way, OP antagonizes GR mediated transactivation effects, as it inhibits bcl-XL expression and GR dependent MMTV-driven gene expression. Interestingly, OP does not inhibit GR nuclear homodimerization but prevents GR-TIF-2 coactivator recruitment. Finally, contrary to most commercial GCs, OP lacks the ability to inhibit apoptosis triggered by chemotherapeutics in mammary tumor cells. Thus, OP emerges as a novel SRGM with potential clinical application as it maintains antiinflammatory activities without inducing chemoresistance.