Δ-9,11 Modification of Glucocorticoids Dissociates Nuclear Factor-κB Inhibitory Efficacy from Glucocorticoid Response Element-Associated Side Effects

Abstract

Glucocorticoids are standard of care for many inflammatory conditions, but chronic use is associated with a broad array of side effects. This has led to a search for dissociative glucocorticoidsdrugs able to retain or improve efficacy associated with transrepression [nuclear factor-B (NF-B) inhibition] but with the loss of side effects associated with transactivation (receptor-mediated transcriptional activation through glucocorticoid response element gene promoter elements). We investigated a glucocorticoid derivative with a ⌬-9,11 modification as a dissociative steroid. The ⌬-9,11 analog showed potent inhibition of tumor necrosis factor-␣-induced NF-B signaling in cell reporter assays, and this transrepression activity was blocked by 17␤-hydroxy-11␤-[4-dimethylamino phenyl]-17␣-[1-propynyl]estra-4,9-dien-3-one (RU-486), showing the requirement for the glucocorticoid receptor (GR). The ⌬-9,11 analog induced the nuclear translocation of GR but showed the loss of transactivation as assayed by GRluciferase constructs as well as mRNA profiles of treated cells. The ⌬-9,11 analog was tested for efficacy and side effects in two mouse models of muscular dystrophy: mdx (dystrophin deficiency), and SJL (dysferlin deficiency). Daily oral delivery of the ⌬-9,11 analog showed a reduction of muscle inflammation and improvements in multiple muscle function assays yet no reductions in body weight or spleen size, suggesting the loss of key side effects. Our data demonstrate that a ⌬-9,11 analog dissociates the GR-mediated transcriptional activities from anti-inflammatory activities. Accordingly, ⌬-9,11 analogs may hold promise as a source of safer therapeutic agents for chronic inflammatory disorders.

Lazaroid U-74389G inhibits the osteoblastic differentiation of IL-1β-indcued aortic valve interstitial cells through glucocorticoid receptor and inhibition of NF-κB pathway

“…Studies have suggested that these anti-inflammatory effects of this class of drugs may be mediated by the inhibition of the anti-inflammatory NF-kB activity [15,16]. Recently, the NF-kB inhibitory activity of two 21-aminosteroids, anecortave and VBP15, were found to be dependent on binding to the glucocorticoid receptor, contrary to previous models of the mechanism of action of this class of drugs [14,17,18]. We sought to determine if the clinically developed 21-aminosteroid, lazaroid U-74389G, also showed GR-dependent NF-kB inhibitory activity, and if this drug inhibited osteoblastic differentiation in AVICs.…”

“…U-74389G has been clinically developed as a potential drug to protect against ischemia/ reperfusion injury of the central nervous and liver, but did not achieve regulatory approval [11,12]. The use of antioxidants in inflammatory diseases has been widely advocated and studies suggested that U-74389G and other 21-aminosteroids are potent inhibitors of the synthesis of several pro-inflammatory cytokines, such as IL-6, IL-8, interferon-g (IFN-g) and tumor necrosis factor-a (TNF-a) [13,14]. Studies have suggested that these anti-inflammatory effects of this class of drugs may be mediated by the inhibition of the anti-inflammatory NF-kB activity [15,16].…”

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

“…This compound, similar to the full GR agonist DEX and other dissociated GCs [38,[41][42][43][44] has been demonstrated to inhibit the LPS/IFN-γ mediated NO formation in a concentrationdependent manner and to repress NOS-2 and COX-2 gene expression in macrophages. 21OH-6,19OP also inhibits TNF-α-induced COX-2 and IL-8 expression in human lung cancer A549 cells.…”

“…In this sense, it was demonstrated that VBP1, a Δ-9,11 analog, was more effective than full agonists, to down-regulate anti-inflammatory genes whose promoters contain both GREs and NF-κB promoter elements, probably due to incapacity of the GR to directly bind DNA [44]. This would not be the case for this rigid compound, since GR/21OH-5,19OP…”

“…As we mentioned above, like others dissociated glucocorticoids 21OH-6,19OP is unable to induce the direct GR/GRE action [44]. In this sense, it was demonstrated that VBP1, a Δ-9,11 analog, was more effective than full agonists, to down-regulate anti-inflammatory genes whose promoters contain both GREs and NF-κB promoter elements, probably due to incapacity of the GR to directly bind DNA [44].…”