title: The effects of dissociated glucocorticoids RU24858 and RU24782 on TPA-induced skin tumor promotion biomarkers in SENCAR mice.
abstract: Glucocorticoids (GCs) are very effective at preventing carcinogen- and tumor promoter-induced skin inflammation, hyperplasia, and mouse skin tumor formation. The effects of GCs are mediated by a well-known transcription factor, the glucocorticoid receptor (GR). GR acts via two different mechanisms: transcriptional regulation that requires DNA-binding (transactivation) and DNA binding-independent protein-protein interactions between GR and other transcription factors, such as nuclear factor kappa B (NF-κB) or activator protein 1 (AP-1; transrepression). We hypothesize that the transrepression activities of the GR are sufficient to suppress skin tumor promotion. We obtained two GCs (RU24858 and RU24782) that have dissociated downstream effects and induce only transrepression activities of the GR in a number of systems. These compounds bind the GR with high affinity and repress AP-1 and NF-κB activities while showing a lack of GR transactivation. RU24858, RU24782, or control full GCs desoximetasone (DES) and fluocinolone acetonide (FA) were applied to the dorsal skin of SENCAR mice prior to application of the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA), two times per week for 2 weeks. DES, FA and RU24858 reversed TPA-induced epidermal hyperplasia and proliferation, while RU24782 treatment had no effect on these markers of skin tumor promotion. All tested compounds decreased TPA-induced c-jun mRNA levels in skin. DES, FA, and RU24858, but not RU24782, were also able to reverse TPA-induced increases in the mRNA levels of COX-2 and iNOS. These findings show that RU24858 but not RU24782 reduced TPA-induced epidermal hyperplasia, proliferation, and inflammation, while both compounds reversed c-jun mRNA increases in the skin.
authors.affiliation: Graduate School of Biomedical Sciences, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
authors.forename: Piotr
authors.initials: P
authors.lastname: Kowalczyk
authors.forename: Jacob J
authors.initials: JJ
authors.lastname: Junco
authors.forename: Magdalena C
authors.initials: MC
authors.lastname: Kowalczyk
authors.forename: Renata
authors.initials: R
authors.lastname: Sosnowska
authors.forename: Olga
authors.initials: O
authors.lastname: Tolstykh
authors.forename: Zbigniew
authors.initials: Z
authors.lastname: Walaszek
authors.forename: Margaret
authors.initials: M
authors.lastname: Hanausek
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Slaga
mesh_terms: D000818:Animals; D021461:Animals, Outbred Strains; D016588:Anticarcinogenic Agents / Q000737:chemistry / Q000494:pharmacology; D015415:Biomarkers; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000235:genetics; D003899:Desoximetasone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D004817:Epidermis / Q000187:drug effects / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D005938:Glucocorticoids / Q000737:chemistry / Q000494:pharmacology*; D006965:Hyperplasia; D015850:Interleukin-6 / Q000235:genetics; D051379:Mice; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics; D012333:RNA, Messenger; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000009:adverse effects
chemical_list: D016588:Anticarcinogenic Agents; D015415:Biomarkers; D005938:Glucocorticoids; D015850:Interleukin-6; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; C000589030:RU24782; C000589029:RU24858; D003899:Desoximetasone; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D013755:Tetradecanoylphorbol Acetate
keywords: SENCAR mice; glucocorticoids; skin tumor promotion