Selective Activator of the Glucocorticoid Receptor Compound A Dissociates Therapeutic and Atrophogenic Effects of Glucocorticoid Receptor Signaling in Skin

Abstract

Background:Glucocorticoids are effective anti-inflammatory drugs widely used in dermatology and for the treatment of blood cancer patients. Unfortunately, chronic treatment with glucocorticoids results in serious metabolic and atrophogenic adverse effects including skin atrophy. Glucocorticoids act via the glucocorticoid receptor (GR), a transcription factor that causes either gene transactivation (TA) or transrepression (TR). Compound A (CpdA), a novel non-steroidal GR ligand, does not promote GR dimerization and TA, retains anti-inflammatory potential but induces fewer metabolic side effects compared to classical glucocorticoids when used systemically. As topical effects of CpdA have not been well studied, this work goal was to compare the anti-inflammatory and side effects of topical CpdA and glucocorticoids and to assess their effect on GR TA and TR in keratinocytes.Methods:We used murine immortalized keratinocytes and F1 C57BlxDBA mice. Effect of glucocorticoid fluocinolone acetonide (FA) and CpdA on gene expression in keratinocytes in vitro and in vivo was evaluated by reverse transcription-PCR. The anti-inflammatory effects were assessed in the model of tumor promoter 12-O-tertradecanoyl-acetate (TPA)-induced dermatitis and in croton oil-induced ear edema test. Skin atrophy was assessed by analysis of epidermal thickness, keratinocyte proliferation, subcutaneous adipose hypoplasia, and dermal changes after chronic treatment with FA and CpdA.Results:In mouse keratinocytes in vitro and in vivo, CpdA did not activate GR-dependent genes but mimicked closely the inhibitory effect of glucocorticoid FA on the expression of inflammatory cytokines and matrix metalloproteinases. When applied topically, CpdA inhibited TPA-induced skin inflammation and hyperplasia. Unlike glucocorticoids, CpdA itself did not induce skin atrophy which correlated with lack of induction of atrophogene regulated in development and DNA damage response 1 (REDD1) causatively involved in skin and muscle steroid-induced atrophy.Conclusions:Overall, our results suggest that CpdA and its derivatives represent novel promising class of anti-inflammatory compounds with reduced topical side effects.

Compound A influences gene regulation of the Dexamethasone-activated glucocorticoid receptor by alternative cofactor recruitment

“…However, using the more physiologically relevant read-out of mRNA expression levels, simultaneous addition resulted, at least for the GR targets tested here, in similar combined effects. Recently, CpdA combined with fluocinolone acetonide (FA), a glucocorticoid used mainly for topical application, was tested on GRE-dependent reporter constructs in murine immortalized keratinocytes 34 . In line with our results using DEX, CpdA strongly suppressed the FA-induced GRE-dependent promotor activity, supporting that the competitive effect is not GC ligand-specific.…”

“…Ligand competition for GR molecules in the cell has been suggested as an underlying mechanism for the combined effect, whereby CpdA could act as a partial GR antagonist 9 , 34 , 35 . In the current work, we present evidence for potential other mechanisms that may help explain the differential effect of the ligand combination compared to DEX alone.…”

Selective glucocorticoid receptor-activating adjuvant therapy in cancer treatments

“…This is in contrast to RU24858 [ 126 ] which still induces GR transactivation in selected cell types [ 135 ]. In mouse models, in contrast to dexamethasone, CpdA shows anti- inflammatory effects and displays reduced GC side-effects because it does not induce hyperglycemia (potentially leading to diabetes) [ 28 , 136 ], hyperinsulinemia [ 130 ] or skin atrophy [ 137 ] and does not elevate AST and ALT enzyme levels (which is a sign of liver toxicity) [ 138 ]. Endogenous cortisol levels are also maintained by CpdA [ 138 ].…”

Glucocorticoid insensitivity by staphylococcal enterotoxin B in keratinocytes of allergic dermatitis is associated with impaired nuclear translocation of the Glucocorticoid Receptor α

“…These properties, as well as the relative long life of a keratinocyte compared with other inflammatory cells such as the neutrophil or eosinophil, make the keratinocyte a potentially important player in the amplification and persistence of inflammatory and immune responses in AD. Several groups have reported that GC exhibits anti-inflammatory eff ;ects in keratinocytes treated with TNFα [32,33], hapten [34], UV-B irradiation [35], IFNg [36], and induces keratinocyte terminal differentiation [37]. However, few investigations have been conducted to determine whether SEB contributes to the resistance to GCs through keratinocytes.…”