title: Salinomycin and other polyether ionophores are a new class of antiscarring agent.
abstract: Although scarring is a component of wound healing, excessive scar formation is a debilitating condition that results in pain, loss of tissue function, and even death. Many tissues, including the lungs, heart, skin, and eyes, can develop excessive scar tissue as a result of tissue injury, chronic inflammation, or autoimmune disease. Unfortunately, there are few, if any, effective treatments to prevent excess scarring, and new treatment strategies are needed. Using HEK293FT cells stably transfected with a TGFβ-dependent luciferase reporter, we performed a small molecule screen to identify novel compounds with antiscarring activity. We discovered that the polyether ionophore salinomycin potently inhibited the formation of scar-forming myofibroblasts. Salinomycin (250 nm) blocked TGFβ-dependent expression of the cardinal myofibroblast products α smooth muscle actin, calponin, and collagen in primary human fibroblasts without causing cell death. Salinomycin blocked phosphorylation and activation of TAK1 and p38, two proteins fundamentally involved in signaling myofibroblast and scar formation. Expression of constitutively active mitogen activated kinase kinase 6, which activates p38 MAPK, attenuated the ability of salinomycin to block myofibroblast formation, demonstrating that salinomycin targets the p38 kinase pathway to disrupt TGFβ signaling. These data identify salinomycin and other polyether ionophores as novel potential antiscarring therapeutics.
authors.affiliation: From the Department of Environmental Medicine and.
authors.forename: Collynn F
authors.initials: CF
authors.lastname: Woeller
authors.affiliation: Flaum Eye Institute, School of Medicine and Dentistry, University of Rochester, Rochester, New York 14642.
authors.forename: Charles W
authors.initials: CW
authors.lastname: O'Loughlin
authors.affiliation: Flaum Eye Institute, School of Medicine and Dentistry, University of Rochester, Rochester, New York 14642.
authors.forename: Elisa
authors.initials: E
authors.lastname: Roztocil
authors.affiliation: Flaum Eye Institute, School of Medicine and Dentistry, University of Rochester, Rochester, New York 14642.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Feldon
authors.affiliation: From the Department of Environmental Medicine and Flaum Eye Institute, School of Medicine and Dentistry, University of Rochester, Rochester, New York 14642 Richard_Phipps@urmc.rochester.edu.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Phipps
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D058628:Myofibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D011714:Pyrans / Q000494:pharmacology*; D054852:Small Molecule Libraries / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000096985:Calponins; D000099151:MAP Kinase Kinase Kinase 7; D000095662:Polyether Polyketides
chemical_list: D000199:Actins; D002135:Calcium-Binding Proteins; D003094:Collagen; D020930:MAP Kinase Kinase Kinases; D008840:Microfilament Proteins; D011714:Pyrans; D054852:Small Molecule Libraries; D016212:Transforming Growth Factor beta; D048051:p38 Mitogen-Activated Protein Kinases; D000096985:Calponins; D000099151:MAP Kinase Kinase Kinase 7; C541116:ACTA2 protein, human; C010327:salinomycin; D000095662:Polyether Polyketides
keywords: Collagen; Fibrosis; MKK6; Myofibroblast; Polyether Ionophores; SMAD Transcription Factor; Salinomycin; TGFβ; p38; p38 MAPK