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Abstract:

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. © 2014 Elsevier Inc.

Registro:

Documento: Artículo
Título: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
Autor:Orqueda, A.J.; Dansey, M.V.; Español, A.; Veleiro, A.S.; Bal De Kier Joffé, E.; Sales, M.E.; Burton, G.; Pecci, A.
Filiación:Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, (C1428EGA), Buenos Aires, Argentina
Departamento de Química Orgánica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, (C1428EGA), Buenos Aires, Argentina
IFIBYNE, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, (C1428EGA), Buenos Aires, Argentina
UMYMFOR (CONICET), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria (C1428EGA), Buenos Aires, Argentina
CEFyBo (CONICET), Universidad de Buenos Aires, Buenos Aires, Argentina
Área Investigación Instituto de Oncología Ángel H. Roffo, Universidad de Buenos Aires, Facultad de Medicina, Paraguay 2155, C1121AB, Buenos Aires, Argentina
Palabras clave:21OH-6,19-epoxyprogesterone; Cyclooxygenase-2; Glucocorticoid receptor; Mitogen activated protein kinase phosphatase-1; Paclitaxel; 21 hydroxy 6,19 epoxyprogesterone; antiinflammatory agent; antineoplastic agent; caspase 3; cyclooxygenase 2; dexamethasone; glucocorticoid receptor; inducible nitric oxide synthase; interleukin 8; mitogen activated protein kinase; paclitaxel; protein bcl xl; tumor necrosis factor alpha; unclassified drug; animal cell; animal experiment; animal model; antiinflammatory activity; article; breast cancer; breast cell; breast epithelium; cancer chemotherapy; cell viability; controlled study; female; histology; human; human cell; metastasis; mouse; nonhuman; peritoneum macrophage; priority journal; protein expression; transactivation; tumor growth; tumor volume; 21OH-6,19-epoxyprogesterone; Cyclooxygenase-2; Dexamethasone (PubChem CID: 5743); Glucocorticoid receptor; Mitogen activated protein kinase phosphatase-1; Paclitaxel; Paclitaxel (PubChem CID: 36314); Animals; Anti-Inflammatory Agents; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cell Line, Transformed; Cell Line, Tumor; Cell Survival; Cells, Cultured; Female; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Macrophages, Peritoneal; Mice; Mice, Inbred BALB C; Neoplasm Proteins; Neoplasm Transplantation; Progesterone; Random Allocation; Receptors, Glucocorticoid; Specific Pathogen-Free Organisms
Año:2014
Volumen:89
Número:4
Página de inicio:526
Página de fin:535
DOI: http://dx.doi.org/10.1016/j.bcp.2014.04.006
Título revista:Biochemical Pharmacology
Título revista abreviado:Biochem. Pharmacol.
ISSN:00062952
CODEN:BCPCA
CAS:caspase 3, 169592-56-7; dexamethasone, 50-02-2; inducible nitric oxide synthase, 501433-35-8; interleukin 8, 114308-91-7; mitogen activated protein kinase, 142243-02-5; paclitaxel, 33069-62-4; protein bcl xl, 151033-38-4
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00062952_v89_n4_p526_Orqueda

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Citas:

---------- APA ----------
Orqueda, A.J., Dansey, M.V., Español, A., Veleiro, A.S., Bal De Kier Joffé, E., Sales, M.E., Burton, G.,..., Pecci, A. (2014) . 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. Biochemical Pharmacology, 89(4), 526-535.
http://dx.doi.org/10.1016/j.bcp.2014.04.006
---------- CHICAGO ----------
Orqueda, A.J., Dansey, M.V., Español, A., Veleiro, A.S., Bal De Kier Joffé, E., Sales, M.E., 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" . Biochemical Pharmacology 89, no. 4 (2014) : 526-535.
http://dx.doi.org/10.1016/j.bcp.2014.04.006
---------- MLA ----------
Orqueda, A.J., Dansey, M.V., Español, A., Veleiro, A.S., Bal De Kier Joffé, E., Sales, M.E., 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" . Biochemical Pharmacology, vol. 89, no. 4, 2014, pp. 526-535.
http://dx.doi.org/10.1016/j.bcp.2014.04.006
---------- VANCOUVER ----------
Orqueda, A.J., Dansey, M.V., Español, A., Veleiro, A.S., Bal De Kier Joffé, E., Sales, M.E., 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. Biochem. Pharmacol. 2014;89(4):526-535.
http://dx.doi.org/10.1016/j.bcp.2014.04.006