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.
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-X(L) 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.
authors.affiliation: Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria (C1428EGA), Buenos Aires, Argentina; IFIBYNE, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria (C1428EGA), Buenos Aires, Argentina. Electronic address: aorqueda@qb.fcen.uba.ar.
authors.forename: Andres J
authors.initials: AJ
authors.lastname: Orqueda
authors.affiliation: Departamento de Química Orgánica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria (C1428EGA), Buenos Aires, Argentina; IFIBYNE, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria (C1428EGA), Buenos Aires, Argentina. Electronic address: virg_dansey@hotmail.com.
authors.forename: M Virginia
authors.initials: MV
authors.lastname: Dansey
authors.affiliation: CEFyBo (CONICET), Universidad de Buenos Aires, Buenos Aires, Argentina. Electronic address: aespan_1999@yahoo.com.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Español
authors.affiliation: Departamento de Química Orgánica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria (C1428EGA), Buenos Aires, Argentina; UMYMFOR (CONICET), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria (C1428EGA), Buenos Aires, Argentina. Electronic address: adrianav@qo.fcen.uba.ar.
authors.forename: Adriana S
authors.initials: AS
authors.lastname: Veleiro
authors.affiliation: Área Investigación Instituto de Oncología Ángel H. Roffo, Facultad de Medicina, Paraguay 2155 (C1121AB), Universidad de Buenos Aires, Buenos Aires, Argentina. Electronic address: balelisa2002@yahoo.com.ar.
authors.forename: Elisa
authors.initials: E
authors.lastname: Bal de Kier Joffé
authors.affiliation: CEFyBo (CONICET), Universidad de Buenos Aires, Buenos Aires, Argentina. Electronic address: malegazpio@yahoo.com.ar.
authors.forename: M Elena
authors.initials: ME
authors.lastname: Sales
authors.affiliation: Departamento de Química Orgánica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria (C1428EGA), Buenos Aires, Argentina; UMYMFOR (CONICET), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria (C1428EGA), Buenos Aires, Argentina. Electronic address: burton@qo.fcen.uba.ar.
authors.forename: Gerardo
authors.initials: G
authors.lastname: Burton
authors.affiliation: Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria (C1428EGA), Buenos Aires, Argentina; IFIBYNE, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria (C1428EGA), Buenos Aires, Argentina. Electronic address: apecci@qb.fcen.uba.ar.
authors.forename: Adali
authors.initials: A
authors.lastname: Pecci
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009368:Neoplasm Transplantation; D011374:Progesterone / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D011897:Random Allocation; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013047:Specific Pathogen-Free Organisms
chemical_list: C108699:21-hydroxy-6,19-oxidoprogesterone; D000893:Anti-Inflammatory Agents; D018931:Antineoplastic Agents, Hormonal; D009363:Neoplasm Proteins; D011965:Receptors, Glucocorticoid; D011374:Progesterone
keywords: 21OH-6,19-epoxyprogesterone; Cyclooxygenase-2; Dexamethasone (PubChem CID: 5743); Glucocorticoid receptor; Mitogen activated protein kinase phosphatase-1; Paclitaxel; Paclitaxel (PubChem CID: 36314)