title: 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 glucocorticoids--drugs able to retain or improve efficacy associated with transrepression [nuclear factor-κB (NF-κB) 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 Δ-9,11 modification as a dissociative steroid. The Δ-9,11 analog showed potent inhibition of tumor necrosis factor-α-induced NF-κB signaling in cell reporter assays, and this transrepression activity was blocked by 17β-hydroxy-11β-[4-dimethylamino phenyl]-17α-[1-propynyl]estra-4,9-dien-3-one (RU-486), showing the requirement for the glucocorticoid receptor (GR). The Δ-9,11 analog induced the nuclear translocation of GR but showed the loss of transactivation as assayed by GR-luciferase constructs as well as mRNA profiles of treated cells. The Δ-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 Δ-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 Δ-9,11 analog dissociates the GR-mediated transcriptional activities from anti-inflammatory activities. Accordingly, Δ-9,11 analogs may hold promise as a source of safer therapeutic agents for chronic inflammatory disorders.
authors: Department of Integrative Systems Biology, George Washington University School of Medicine and Health Sciences, Washington, District of Columbia, USA.
authors: Andreas R
authors: AR
authors: Baudy
authors: Erica K M
authors: EK
authors: Reeves
authors: Jesse M
authors: JM
authors: Damsker
authors: Christopher
authors: C
authors: Heier
authors: Lindsay M
authors: LM
authors: Garvin
authors: Blythe C
authors: BC
authors: Dillingham
authors: John
authors: J
authors: McCall
authors: Sree
authors: S
authors: Rayavarapu
authors: Zuyi
authors: Z
authors: Wang
authors: Jack H
authors: JH
authors: Vandermeulen
authors: Arpana
authors: A
authors: Sali
authors: Vanessa
authors: V
authors: Jahnke
authors: Stephanie
authors: S
authors: Duguez
authors: Debra
authors: D
authors: DuBois
authors: Mary C
authors: MC
authors: Rose
authors: Kanneboyina
authors: K
authors: Nagaraju
authors: Eric P
authors: EP
authors: Hoffman
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D005938:Glucocorticoids / Q000009:adverse effects* / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D018345:Mice, Knockout; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020218:Response Elements / Q000187:drug effects* / Q000502:physiology; D013154:Spleen / Q000187:drug effects / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D005938:Glucocorticoids; D016328:NF-kappa B; C016780:11-nor-delta(9)-tetrahydrocannabinol-9-carboxylic acid; D013759:Dronabinol