Anti-inflammatory Effects of Mapracorat, a Novel Selective Glucocorticoid Receptor Agonist, Is Partially Mediated by MAP Kinase Phosphatase-1 (MKP-1)

Vollmer, Thomas; Stockhausen, Anthony; Zhang, Jinzhong

doi:10.1074/jbc.m112.400671

Cited by 34 publications

(18 citation statements)

References 66 publications

(87 reference statements)

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“…In fact, our results are similar to those reported with Mapracorat, a non-steroidal GR selective ligand that inhibits COX-2 expression and p38 activation in RAW 264.7 cells [37] and IL-6, IL-8…”

Section: Discussionsupporting

confidence: 91%

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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Dansey

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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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Section: Discussionsupporting

confidence: 91%

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

Dansey

Español

et al. 2014

Biochemical Pharmacology

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“…Contrary to DUSP1 being a major effec-tor of glucocorticoid action (4,38), the current data suggests a transient, more minor, role for DUSP1 compared with DUSP1-independent mechanisms of repression. Therefore, whereas the up-regulation of DUSP1 by novel NR3C1 receptor modulators has correlated with repressive or anti-inflammatory effects (49,50), this may not hold for all such agonists. The current data emphasize the need to continue the characterization of glucocorticoid-induced effector responses and to explore their roles relative to known effectors such as DUSP1.…”

Section: Discussionmentioning

confidence: 99%

Roles for the Mitogen-activated Protein Kinase (MAPK) Phosphatase, DUSP1, in Feedback Control of Inflammatory Gene Expression and Repression by Dexamethasone

Shah

King

Chandrasekhar

et al. 2014

Journal of Biological Chemistry

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Background: Inflammatory gene expression is reduced by anti-inflammatory glucocorticoids. Results: With an inflammatory stimulus, glucocorticoids enhance expression of the phosphatase, DUSP1. This plays a transient role in the repression of some inflammatory genes. Conclusion: Glucocorticoids repress inflammatory gene expression via DUSP1-dependent and -independent mechanisms. Significance: Consideration of both DUSP1 and DUSP1-independent effectors is necessary to improve anti-inflammatory glucocorticoid action.

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“…Steroids, such as hydrocortisone and prednisolone, are strong anti-inflammatory drugs, which inhibit the functions of T cells, B cells and macrophages (Vollmer et al 2012). LPS-activated macrophages were treated with MH for 24 h to determine its effects on COX-2-mediated PGF 1a production (a).…”

Section: Discussionmentioning

confidence: 99%

Validation of cyclooxygenase-2 as a direct anti-inflammatory target of 4-O-methylhonokiol in zymosan-induced animal models

et al. 2014

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4-O-methylhonokiol (MH) is known to inhibit inflammation by partially understood mechanisms. Here, the anti-inflammatory mechanisms of MH were examined using enzymatic, cellular, and animal assays. In enzymatic assays, MH inhibited COX-2 activity with an IC50 of 0.062 μM, and also COX-1 with an IC50 of 2.4 μM. In cellular assays, MH was immunotoxic above 10 μM. At non-toxic concentrations (below 3 μM), MH strongly inhibited COX-2-mediated prostaglandin production with an IC50 of 0.1 μM, whereas did not or slightly affect other functions of B cells, T cells, dendritic cells, and macrophages. In an animal model, MH inhibited the increase in footpad thickness and popliteal lymph node weight in zymosan-injected mice. When analyzed the draining pLNs of zymosan-injected mice on day 5, MH inhibited the overall inflammatory responses. However, MH inhibited cyclooxygenase (COX)-2-mediated prostaglandin production without affecting tumor necrosis factor-α production in inflamed tissues within 6 h after zymosan injection. In summary, our data suggest that COX-2 may be a direct anti-inflammatory target of MH in vitro and in vivo.

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Anti-inflammatory Effects of Mapracorat, a Novel Selective Glucocorticoid Receptor Agonist, Is Partially Mediated by MAP Kinase Phosphatase-1 (MKP-1)

Cited by 34 publications

References 66 publications

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

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

Roles for the Mitogen-activated Protein Kinase (MAPK) Phosphatase, DUSP1, in Feedback Control of Inflammatory Gene Expression and Repression by Dexamethasone

Validation of cyclooxygenase-2 as a direct anti-inflammatory target of 4-O-methylhonokiol in zymosan-induced animal models

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