IFIBYNE   05513
INSTITUTO DE FISIOLOGIA, BIOLOGIA MOLECULAR Y NEUROCIENCIAS
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
21-hidroxi-6,19-epoxyprogesterone: A lead compound with dissociated glucocorticoid activities
Autor/es:
ORQUEDA, A; PRESMAN, D.M.; ALVAREZ, L; KORDON, E; BURTON G.; PECCI A.
Lugar:
Los Cocos, Cordoba
Reunión:
Workshop; SISTAM 2010; 2010
Resumen:
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-a 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, different from 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.