title: Identification of select glucocorticoids as Smoothened agonists: potential utility for regenerative medicine.
abstract: Regenerative medicine holds the promise of replacing damaged tissues largely by stem cell activation. Hedgehog signaling through the plasma membrane receptor Smoothened (Smo) is an important process for regulating stem cell proliferation. The development of Hedgehog-related therapies has been impeded by a lack of US Food and Drug Administration (FDA)-approved Smo agonists. Using a high-content screen with cells expressing Smo receptors and a beta-arrestin2-GFP reporter, we identified four FDA-approved drugs, halcinonide, fluticasone, clobetasol, and fluocinonide, as Smo agonists that activate Hedgehog signaling. These drugs demonstrated an ability to bind Smo, promote Smo internalization, activate Gli, and stimulate the proliferation of primary neuronal precursor cells alone and synergistically in the presence of Sonic Hedgehog protein. Halcinonide, fluticasone, clobetasol, and fluocinonide provide an unprecedented opportunity to develop unique clinical strategies to treat Hedgehog-dependent illnesses.
authors.affiliation: Departments of Medicine, Surgery, and Cell Biology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Jiangbo
authors.initials: J
authors.lastname: Wang
authors.forename: Jiuyi
authors.initials: J
authors.lastname: Lu
authors.forename: Michael C
authors.initials: MC
authors.lastname: Bond
authors.forename: Minyong
authors.initials: M
authors.lastname: Chen
authors.forename: Xiu-Rong
authors.initials: XR
authors.lastname: Ren
authors.forename: H Kim
authors.initials: HK
authors.lastname: Lyerly
authors.forename: Larry S
authors.initials: LS
authors.lastname: Barak
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D019390:Arrestins; D015153:Blotting, Western; D002460:Cell Line; D049109:Cell Proliferation; D002990:Clobetasol / Q000494:pharmacology; D005447:Fluocinonide / Q000494:pharmacology; D000068298:Fluticasone; D005938:Glucocorticoids / Q000494:pharmacology*; D049452:Green Fluorescent Proteins; D006206:Halcinonide / Q000494:pharmacology; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D015394:Molecular Structure; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D044968:Regenerative Medicine / Q000379:methods*; D015398:Signal Transduction / Q000502:physiology*; D000072086:Smoothened Receptor; D013234:Stem Cells / Q000378:metabolism / Q000502:physiology*; D000071557:beta-Arrestins
chemical_list: D000730:Androstadienes; D019390:Arrestins; D005938:Glucocorticoids; D053823:Hedgehog Proteins; D043562:Receptors, G-Protein-Coupled; C491023:SMO protein, human; D000072086:Smoothened Receptor; D000071557:beta-Arrestins; D049452:Green Fluorescent Proteins; D005447:Fluocinonide; D002990:Clobetasol; D000068298:Fluticasone; D006206:Halcinonide