Strategies and Compounds to Circumvent Glucocorticoid-Induced Side Effects

Luypaert, Astrid; Berghe, Wim Vanden; Tavernier, Jan; Libert, Claude; Bosscher, Karolien De

doi:10.1007/978-3-319-77658-3_13

Cited by 4 publications

(4 citation statements)

References 111 publications

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“…Citations in previous published reviews were checked to select further pertinent studies, if any. 5,[15][16][17][18] Two reviewers independently checked the relevant studies identified from literature searches obtained from the abovementioned databases. The studies were selected in agreement with previously mentioned criteria, and any difference in opinion about eligibility was resolved by consensus.…”

Section: Search Strategymentioning

confidence: 99%

<p>Experimental Glucocorticoid Receptor Agonists for the Treatment of Asthma: A Systematic Review</p>

Rogliani¹,

Ritondo²,

Puxeddu³

et al. 2020

JEP

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Inhaled corticosteroids (ICSs) are considered the cornerstone of asthma treatment. Despite the solid evidence documenting the efficacy and safety of ICSs at the level of the airways, their use can be affected by pulmonary and systemic adverse events (AEs) when administered chronically and/or at high doses. Thus, there is a pharmacological and medical need for new glucocorticoid (GC) receptor (GR) ligands with a more favorable therapeutic index, in order to overcome the shortcomings of currently available ICSs. The therapeutic profile of GCs can be improved by enhancing genomic mechanisms mediated by transrepression, which is assumed to be responsible for several anti-inflammatory and immunomodulatory actions, rather than transactivation, which causes most of the GC-associated AEs. It was assumed that an independent modulation of the molecular mechanisms underlying transactivation and transrepression could translate into the dissociation of beneficial effects from AEs. Therefore, current research is looking for GCs that are able to elicit prevalently transrepression with negligible transactivating activity. These compounds are known as selective glucocorticoid receptor agonists (SEGRAs). In this review, experimental GR agonists currently in pre-clinical and clinical development for the treatment of asthma have been systematically assessed. Several compounds are currently under pre-clinical development, but only three novel experimental GR agonists (GW870086X, AZD5423, AZD7594) seem to have some potential therapeutic relevance and have entered clinical trials for the treatment of asthma. Since data from pre-clinical studies have not always been confirmed in clinical investigations, well-designed randomized controlled trials are needed in asthmatic patients to confirm the potentially positive benefit/risk ratio of each specific SEGRA and to optimize the development strategy of these agents in respiratory medicine.

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Section: Search Strategymentioning

confidence: 99%

<p>Experimental Glucocorticoid Receptor Agonists for the Treatment of Asthma: A Systematic Review</p>

Rogliani¹,

Ritondo²,

Puxeddu³

et al. 2020

JEP

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“…The main mechanisms via which GC drive the transcription and regulation of multiple genes are direct DNA binding, tethering and composite binding (38–40) (Figure 1). In the nucleus, GRα is able to modulate gene transcription through binding to target sequences termed GC-response elements (GREs), largely in the cis-regulatory region of target genes (41).…”

Section: The Mechanism Of Gc Action In the Treatment Of Slementioning

confidence: 99%

“…The binding of the GRα to the GRE can also cause conformational changes in the GR which causes the recruitment of cofactors and coregulators to the site with the ability to modulate and alter the transcriptional rate of many target genes (35, 37). Direct DNA binding of the GRα to GREs results in the induction of gene expression and causes the transcription of multiple genes, including anti-inflammatory genes such as IL-10 and IL-1 receptor antagonist (38, 40) as well as GC-induced leucine zipper (GILZ). GRα can also directly bind to negative GREs (nGRE), which results in suppression of the transcription of several proinflammatory modulators and cytokines including interleukin (IL)-1β (38, 40, 42).…”

Section: The Mechanism Of Gc Action In the Treatment Of Slementioning

confidence: 99%

“…Direct DNA binding of the GRα to GREs results in the induction of gene expression and causes the transcription of multiple genes, including anti-inflammatory genes such as IL-10 and IL-1 receptor antagonist (38, 40) as well as GC-induced leucine zipper (GILZ). GRα can also directly bind to negative GREs (nGRE), which results in suppression of the transcription of several proinflammatory modulators and cytokines including interleukin (IL)-1β (38, 40, 42). Another form of gene repression, termed tethering, is mediated by the ability of GRs to tether to pro-inflammatory transcription factors such as the p65 subunit of nuclear factor kappa B (NF-κB) and activator protein 1 (AP-1), antagonizing their function (35, 43–45).…”

Section: The Mechanism Of Gc Action In the Treatment Of Slementioning

confidence: 99%

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Could GILZ Be the Answer to Glucocorticoid Toxicity in Lupus?

2019

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Glucocorticoids (GC) are used globally to treat autoimmune and inflammatory disorders. Their anti-inflammatory actions are mainly mediated via binding to the glucocorticoid receptor (GR), creating a GC/GR complex, which acts in both the cytoplasm and nucleus to regulate the transcription of a host of target genes. As a result, signaling pathways such as NF-κB and AP-1 are inhibited, and cell activation, differentiation and survival and cytokine and chemokine production are suppressed. However, the gene regulation by GC can also cause severe side effects in patients. Systemic lupus erythematosus (SLE or lupus) is a multisystem autoimmune disease, characterized by a poorly regulated immune response leading to chronic inflammation and dysfunction of multiple organs, for which GC is the major current therapy. Long-term GC use, however, can cause debilitating adverse consequences for patients including diabetes, cardiovascular disease and osteoporosis and contributes to irreversible organ damage. To date, there is no alternative treatment which can replicate the rapid effects of GC across multiple immune cell functions, effecting disease control during disease flares. Research efforts have focused on finding alternatives to GC, which display similar immunoregulatory actions, without the devastating adverse metabolic effects. One potential candidate is the glucocorticoid-induced leucine zipper (GILZ). GILZ is induced by low concentrations of GC and is shown to mimic the action of GC in several inflammatory processes, reducing immunity and inflammation in in vitro and in vivo studies. Additionally, GILZ has, similar to the GC-GR complex, the ability to bind to both NF-κB and AP-1 as well as DNA directly, to regulate immune cell function, while potentially lacking the GC-related side effects. Importantly, in SLE patients GILZ is under-expressed and correlates negatively with disease activity, suggesting an important regulatory role of GILZ in SLE. Here we provide an overview of the actions and use of GC in lupus, and discuss whether the regulatory mechanisms of GILZ could lead to the development of a novel therapeutic for lupus. Increased understanding of the mechanisms of action of GILZ, and its ability to regulate immune events leading to lupus disease activity has important clinical implications for the development of safer anti-inflammatory therapies.

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Characterization of a novel non-steroidal glucocorticoid receptor agonist optimized for topical treatment

Eirefelt

Stahlhut

Svitacheva

et al. 2022

Sci Rep

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Glucocorticoids (GCs) are commonly used topical treatments for skin diseases but are associated with both local and systemic side effects. In this study, we describe a selective non-steroidal glucocorticoid receptor (GR) agonist for topical use, LEO 134310, which is rapidly deactivated in the blood resulting in low systemic exposure and a higher therapeutic index in the TPA-induced skin inflammation mouse model compared with betamethasone valerate (BMV) and clobetasol propionate (CP). Selectivity of LEO 134310 for GR was confirmed within a panel of nuclear receptors, including the mineralocorticoid receptor (MR), which has been associated with induction of skin atrophy. Topical treatment with LEO 134310 in minipigs did not result in any significant reduction in epidermal thickness in contrast to significant epidermal thinning induced by treatment with BMV and CP. Thus, the profile of LEO 134310 may potentially provide an effective and safer treatment option for skin diseases compared with currently used glucocorticoids.

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Strategies and Compounds to Circumvent Glucocorticoid-Induced Side Effects

Cited by 4 publications

References 111 publications

<p>Experimental Glucocorticoid Receptor Agonists for the Treatment of Asthma: A Systematic Review</p>

<p>Experimental Glucocorticoid Receptor Agonists for the Treatment of Asthma: A Systematic Review</p>

Could GILZ Be the Answer to Glucocorticoid Toxicity in Lupus?

Characterization of a novel non-steroidal glucocorticoid receptor agonist optimized for topical treatment

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