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

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 dr...

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Autores principales:	Orqueda, Andrés Javier, Dansey, Maria Virginia, Español, Alejandro Javier, Veleiro, Adriana Silvia, Burton, Gerardo, Pecci, Adali
Publicado:	2014
Materias:	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 Dexamethasone (PubChem CID: 5743) 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
Acceso en línea:	https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00062952_v89_n4_p526_Orqueda http://hdl.handle.net/20.500.12110/paper_00062952_v89_n4_p526_Orqueda
Aporte de:	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) de Universidad de Buenos Aires

id	paper:paper_00062952_v89_n4_p526_Orqueda
record_format	dspace
institution	Universidad de Buenos Aires
institution_str	I-28
repository_str	R-134
collection	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA)
topic	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
spellingShingle	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 Orqueda, Andrés Javier Dansey, Maria Virginia Español, Alejandro Javier Veleiro, Adriana Silvia Burton, Gerardo Pecci, Adali 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
topic_facet	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
description	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.
author	Orqueda, Andrés Javier Dansey, Maria Virginia Español, Alejandro Javier Veleiro, Adriana Silvia Burton, Gerardo Pecci, Adali
author_facet	Orqueda, Andrés Javier Dansey, Maria Virginia Español, Alejandro Javier Veleiro, Adriana Silvia Burton, Gerardo Pecci, Adali
author_sort	Orqueda, Andrés Javier
title	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
title_short	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
title_full	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
title_fullStr	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
title_full_unstemmed	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
title_sort	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
publishDate	2014
url	https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00062952_v89_n4_p526_Orqueda http://hdl.handle.net/20.500.12110/paper_00062952_v89_n4_p526_Orqueda
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spelling	paper:paper_00062952_v89_n4_p526_Orqueda2023-06-08T14:30:37Z 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, Andrés Javier Dansey, Maria Virginia Español, Alejandro Javier Veleiro, Adriana Silvia Burton, Gerardo Pecci, Adali 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 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. Fil:Orqueda, A.J. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Dansey, M.V. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Español, A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Veleiro, A.S. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Burton, G. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Pecci, A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. 2014 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00062952_v89_n4_p526_Orqueda http://hdl.handle.net/20.500.12110/paper_00062952_v89_n4_p526_Orqueda

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

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