nsc-668036 and Pulmonary-Fibrosis

In this study, we determined the effects of transforming growth factor-beta (TGF-β) and Wnt/β-catenin signaling on myofibroblast differentiation of NIH/3T3 fibroblasts in vitro and evaluated the therapeutic efficacy of NSC668036 in bleomycin-induced pulmonary fibrosis murine model. In vitro study, NSC668036, a small organic inhibitor of the PDZ domain in Dvl, suppressed β-catenin-driven gene transcription and abolished TGF-β1-induced migration, expression of collagen I and α-smooth muscle actin (α-SMA) in fibroblasts. In vivo study, we found that NSC668036 significantly suppressed accumulation of collagen I, α-SMA, and TGF-β1 but increased the expression of CK19, Occludin and E-cadherin that can inhibit pulmonary fibrogenesis. Because fibrotic lung exhibit aberrant activation of Wnt/β-catenin signaling, these data collectively suggest that inhibition of Wnt/β-catenin signaling at the Dvl level may be an effective approach to the treatment of fibrotic lung diseases.

Topics: Adaptor Proteins, Signal Transducing; Animals; Antibiotics, Antineoplastic; beta Catenin; Bleomycin; Blotting, Western; Cadherins; Cell Proliferation; Cells, Cultured; Depsipeptides; Dishevelled Proteins; Fibroblasts; Flow Cytometry; Fluorescent Antibody Technique; Immunoenzyme Techniques; Male; Mice; Mice, Inbred C57BL; NIH 3T3 Cells; PDZ Domains; Phosphoproteins; Pulmonary Fibrosis; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Transforming Growth Factor beta1