Hemisuccinate of 21‐Hydroxy‐6,19‐Epoxyprogesterone: A Tissue‐Specific Modulator of the Glucocorticoid Receptor

Álvarez, Lautaro D.; Martí, Marcelo A.; Veleiro, Adriana S.; Misico, Rosana I.; Estrin, Darı́o A.; Pecci, Adalı́; Burton, Gerardo

doi:10.1002/cmdc.200800256

Cited by 18 publications

(22 citation statements)

References 40 publications

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“…Regarding 21HS-6,19OP, those previous results led us to propose that the hemisuccinate moiety might play a key role in stabilizing the receptor active conformation of the dimerization interface, reversing the changes observed with the antagonist 21OH-6,19OP [48].…”

Section: Introductionmentioning

confidence: 85%

“…21OH-6,19OP is a specific GR antagonist that lacks the bulky substituent at C-11 found in active antagonists of the GR [45]–[47]. The introduction of a hemisuccinate group at the 21-position of this passive antiglucocorticoid leads to a compound (21HS-6,19OP), which behaves like an agonist of GR action in direct transactivation assays [48].…”

Section: Introductionmentioning

confidence: 99%

“…Taking into account that the understanding of the molecular role played by different ligands on coactivator recruitment and dimer formation is related to the ability of predicting the overall conformational change of the receptor upon ligand binding; we had previously used Molecular Dynamics (MD) simulation to evaluate the dynamic behavior of GR LBD-Dex, GR LBD-21OH-6,19OP and GR LBD-21HS-6,19OP complexes [47], [48]. These results showed that in the receptor bound to 21OH-6,19OP the average position of the loop between helices 1 and 3 (H1–H3 loop) adopts a markedly different conformation compared to the GR LBD–Dex complex.…”

Section: Introductionmentioning

confidence: 99%

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Insights on Glucocorticoid Receptor Activity Modulation through the Binding of Rigid Steroids

et al. 2010

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BackgroundThe glucocorticoid receptor (GR) is a transcription factor that regulates gene expression in a ligand-dependent fashion. This modular protein is one of the major pharmacological targets due to its involvement in both cause and treatment of many human diseases. Intense efforts have been made to get information about the molecular basis of GR activity.Methodology/Principal FindingsHere, the behavior of four GR-ligand complexes with different glucocorticoid and antiglucocorticoid properties were evaluated. The ability of GR-ligand complexes to oligomerize in vivo was analyzed by performing the novel Number and Brightness assay. Results showed that most of GR molecules form homodimers inside the nucleus upon ligand binding. Additionally, in vitro GR-DNA binding analyses suggest that ligand structure modulates GR-DNA interaction dynamics rather than the receptor's ability to bind DNA. On the other hand, by coimmunoprecipitation studies we evaluated the in vivo interaction between the transcriptional intermediary factor 2 (TIF2) coactivator and different GR-ligand complexes. No correlation was found between GR intranuclear distribution, cofactor recruitment and the homodimerization process. Finally, Molecular determinants that support the observed experimental GR LBD-ligand/TIF2 interaction were found by Molecular Dynamics simulation.Conclusions/SignificanceThe data presented here sustain the idea that in vivo GR homodimerization inside the nucleus can be achieved in a DNA-independent fashion, without ruling out a dependent pathway as well. Moreover, since at least one GR-ligand complex is able to induce homodimer formation while preventing TIF2 coactivator interaction, results suggest that these two events might be independent from each other. Finally, 21-hydroxy-6,19-epoxyprogesterone arises as a selective glucocorticoid with potential pharmacological interest. Taking into account that GR homodimerization and cofactor recruitment are considered essential steps in the receptor activation pathway, results presented here contribute to understand how specific ligands influence GR behavior.

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Section: Introductionmentioning

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Insights on Glucocorticoid Receptor Activity Modulation through the Binding of Rigid Steroids

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“…Upon GR binding, 19OP activates translocation of the receptor to the nucleus and its dimerization [15]. This rigid steroid has the potential function of a dissociated GC since it inhibits Rel A and activator protein 1 (AP-1) dependent gene expression in BHK and Cos-1 cells [15][16] but it is unable to induce tyrosine aminotransferase or to increase glycogen deposits in rat liver [14] and MMTV-LUC reporter gene expression in L929 fibroblasts [17] and in Cos-1 cells transfected with the GR receptor [16].…”

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confidence: 99%

“…21OH-6,19OP also behaves as a strong anti-glucocorticoid, blocking DEX-dependent apoptosis in thymocytes [17].…”

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confidence: 99%

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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et al. 2014

Biochemical Pharmacology

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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), 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.

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Structure of the Glucocorticoid Receptor, a Flexible Protein That Can Adapt to Different Ligands

et al. 2010

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Hemisuccinate of 21‐Hydroxy‐6,19‐Epoxyprogesterone: A Tissue‐Specific Modulator of the Glucocorticoid Receptor

Cited by 18 publications

References 40 publications

Insights on Glucocorticoid Receptor Activity Modulation through the Binding of Rigid Steroids

Insights on Glucocorticoid Receptor Activity Modulation through the Binding of Rigid Steroids

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

Structure of the Glucocorticoid Receptor, a Flexible Protein That Can Adapt to Different Ligands

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