Test systems for the determination of glucocorticoid receptor ligand induced skin atrophy

Schoepe, Stefanie; Schäcke, Heike; Asadullah, Khusru

doi:10.4161/derm.15065

Cited by 11 publications

(12 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although we observed no atrophogenic activity of dasatinib and LCB 03‐0110 in our test using hairless mice, this could also vary in humans. The hairless rodent model is known to be highly sensitive to atrophy assay compared with humans 38 . However, there are clear anatomical differences between rodent and human skin 39 .…”

Section: Discussionmentioning

confidence: 99%

Topical administration of the pan-Src kinase inhibitors, dasatinib and LCB 03-0110, prevents allergic contact dermatitis in mice

Jung

Sun

Ryu

et al. 2012

British Journal of Dermatology

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 99%

Topical administration of the pan-Src kinase inhibitors, dasatinib and LCB 03-0110, prevents allergic contact dermatitis in mice

Jung

Sun

Ryu

et al. 2012

British Journal of Dermatology

View full text Add to dashboard Cite

show abstract

“…In contrast to steroids, CpdA did not induce muscle waste when it was used systemically in mdx mice [ 67 ]. CpdA also did not induce skin atrophy in rats and mice when applied topically [ 107 , 108 ], which we have correlated with its inability to induce atrophogene REDD1 in skin (Budunova, Haegeman, unpublished). In addition, the inhibitory effect of CpdA on collagen type I and III gene expression in skin, the key molecular change related to atrophy in dermis, was favorably diminished when compared to Gcs [ 107 , 108 ].…”

Section: The Biological Activity Of Cpda- Potential Clinical Benefitsmentioning

confidence: 75%

Discovery of Compound A - a selective activator of the glucocorticoid receptor with anti-inflammatory and anti-cancer activity

et al. 2015

View full text Add to dashboard Cite

Glucocorticoids are among the most effective anti-inflammatory drugs, and are widely used for cancer therapy. Unfortunately, chronic treatment with glucocorticoids results in multiple side effects. Thus, there was an intensive search for selective glucocorticoid receptor (GR) activators (SEGRA), which retain therapeutic potential of glucocorticoids, but with fewer adverse effects. GR regulates gene expression by transactivation (TA), by binding as homodimer to gene promoters, or transrepression (TR), via diverse mechanisms including negative interaction between monomeric GR and other transcription factors. It is well accepted that metabolic and atrophogenic effects of glucocorticoids are mediated by GR TA. Here we summarized the results of extensive international collaboration that led to discovery and characterization of Compound A (CpdA), a unique SEGRA with a proven “dissociating” GR ligand profile, preventing GR dimerization and shifting GR activity towards TR both in vitro and in vivo. We outlined here the unusual story of compound's discovery, and presented a comprehensive overview of CpdA ligand properties, its anti-inflammatory effects in numerous animal models of inflammation and autoimmune diseases, as well as its anti-cancer effects. Finally, we presented mechanistic analysis of CpdA and glucocorticoid effects in skin, muscle, bone, and regulation of glucose and fat metabolism to explain decreased CpdA side effects compared to glucocorticoids. Overall, the results obtained by our and other laboratories underline translational potential of CpdA and its derivatives for treatment of inflammation, autoimmune diseases and cancer.

show abstract

“…For human volunteers, we used one of the most potent steroids, clobetasol propionate (CBP, 0.05% cream) [5,29]. KLK6 mRNA expression was strongly induced in human skin after 2 weeks of treatment with CBP (Figure 1c).…”

Section: Resultsmentioning

confidence: 99%

Important role of kallikrein 6 for the development of keratinocyte proliferative resistance to topical glucocorticoids

et al. 2016

View full text Add to dashboard Cite

One of the major adverse effects of topical glucocorticoids is cutaneous atrophy often followed by development of resistance to steroids (tachyphylaxis). Previously we showed that after two weeks, interfollicular mouse keratinocytes acquired resistance to anti-proliferative effects of glucocorticoid fluocinolone acetonide (FA). One of the top genes activated by FA during tachyphylaxis was Klk6 encoding kallikrein-related peptidase 6, known to enhance keratinocyte proliferation. KLK6 was also strongly induced by chronic glucocorticoids in human skin. Double immunostaining showed that KLK6+ keratinocytes, localized in suprabasal layer of mouse skin, were frequently adjacent to proliferating 5-bromo-2'-deoxyuridine-positive basal keratinocytes. We used KLK6 knockout (KO) mice to evaluate KLK6 role in skin regeneration after steroid-induced atrophy. KLK6 KOs had thinner epidermis and decreased keratinocyte proliferation. The keratinocytes in wild type and KLK6 KO epidermis were equally sensitive to acute anti-proliferative effect of FA. However, the development of proliferative resistance during chronic treatment was reduced in KO epidermis. This was not due to the changes in glucocorticoid receptor (GR) expression or function as GR protein level and induction of GR-target genes were similar in wild type and KLK6 KO skin. Overall, these results suggest a novel mechanism of epidermal regeneration after glucocorticoid-induced atrophy via KLK6 activation.

show abstract

Test systems for the determination of glucocorticoid receptor ligand induced skin atrophy

Cited by 11 publications

References 48 publications

Topical administration of the pan-Src kinase inhibitors, dasatinib and LCB 03-0110, prevents allergic contact dermatitis in mice

Topical administration of the pan-Src kinase inhibitors, dasatinib and LCB 03-0110, prevents allergic contact dermatitis in mice

Discovery of Compound A - a selective activator of the glucocorticoid receptor with anti-inflammatory and anti-cancer activity

Important role of kallikrein 6 for the development of keratinocyte proliferative resistance to topical glucocorticoids

Contact Info

Product

Resources

About