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Artículo

The rigid steroid 21-hydroxy-6,19-epoxyprogesterone (21OH-6,19OP) is a dissociated glucocorticoid receptor modulator potentially useful as a novel coadjuvant in breast cancer chemotherapy

Orqueda, Andres JavierIcon ; Dansey, Maria VirginiaIcon ; Español, Alejandro JavierIcon ; Veleiro, Adriana SilviaIcon ; Bal, Elisa DoraIcon ; Sales, Maria ElenaIcon ; Burton, GerardoIcon ; Pecci, AdaliIcon
Fecha de publicación: 06/2014
Editorial: Elsevier Ireland
Revista: Biochemical Pharmacology
ISSN: 0006-2952
Idioma: Inglés
Tipo de recurso: Artículo publicado
Clasificación temática:
Otras Medicina Básica

Resumen

Glucocorticoids (GCs) are steroid hormones widely used as coadjuvants in the treatment of solid tumors due to their anti-inflammatory effects. However, evidence show that they also may induce chemotherapy resistance, probably through their capacity to inhibit apoptosis triggered by antineoplastic drugs. GCs exert their action by regulating gene expression throughout two main mechanisms: transactivation, where the activated glucocorticoid receptor (GR) directly binds to certain genes; and transrepression, an indirect mechanism by which GR regulates other transcription factors activities. Recently, our group has shown that the rigid steroid 21-hydroxy-6,19-epoxyprogesterone (21OH-6,19OP) is a selective GR ligand that behaves as an agonist in transrepression assays and as an antagonist in transactivation ones. Here, we have evaluated the anti-inflammatory activity of 21OH-6,19OP, its capacity to generate chemoresistance, as well as its mechanism of action. We found that 21OH-6,19OP inhibits nitrites formation and the inducible nitric oxide synthase (Nos-2) expression in macrophages. It also blocks the expression of both cyclooxygenase-2 (COX-2) and interleukin-8 (IL-8) triggered by tumor necrosis factor-alpha (TNF-α) in epithelial lung cancer cells. However, contrary to dexamethasone (DEX), 21OH-6,19OP neither reverts the paclitaxel-induced caspase-3 activity, nor induces the anti-apoptotic Bcl-XL gene expression in murine tumor mammary epithelial cells; and importantly, it lacks GCs-associated chemoresistance in a mouse mammary tumor model. Together, our findings suggest that 21OH-6,19OP behaves as a dissociated GC that keeps anti-inflammatory action without affecting the apoptotic process triggered by chemotherapeutic drugs. For these reasons, this steroid may become a putative novel coadjuvant in the treatment of breast cancer.
Palabras clave: Glucocorticoid Receptor , 21oh-6 , 19-Epoxyprogesterone , Cyclooxygenase-2 , Mitogen Activated Protein Kinase Phosphatase-1 , Paclitaxel , Breast , Cancer , Steroid , Chemotherapy
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info:eu-repo/semantics/openAccess Excepto donde se diga explícitamente, este item se publica bajo la siguiente descripción: Atribución-NoComercial-SinDerivadas 2.5 Argentina (CC BY-NC-ND 2.5 AR)
Identificadores
URI: http://hdl.handle.net/11336/14004
URL: http://www.sciencedirect.com/science/article/pii/S0006295214002305
DOI: http://dx.doi.org/10.1016/j.bcp.2014.04.006
Colecciones
Articulos(CEFYBO)
Articulos de CENTRO DE ESTUDIOS FARMACOLOGICOS Y BOTANICOS
Articulos(IFIBYNE)
Articulos de INST.DE FISIOL., BIOL.MOLECULAR Y NEUROCIENCIAS
Articulos(UMYMFOR)
Articulos de UNID.MICROANAL.Y MET.FISICOS EN QUIM.ORG.(I)
Citación
Orqueda, Andres Javier; Dansey, Maria Virginia; Español, Alejandro Javier; Veleiro, Adriana Silvia; Bal, Elisa Dora; et al.; The rigid steroid 21-hydroxy-6,19-epoxyprogesterone (21OH-6,19OP) is a dissociated glucocorticoid receptor modulator potentially useful as a novel coadjuvant in breast cancer chemotherapy; Elsevier Ireland; Biochemical Pharmacology; 89; 4; 6-2014; 526-535
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