title: Inhibition of TGF-β signaling by the fungal lactones (S)-curvularin, dehydrocurvularin, oxacyclododecindione and galiellalactone.
abstract: TGF-β is a multifunctional cytokine that regulates cell proliferation, differentiation, apoptosis and extracellular matrix production. Deregulation of TGF-β production or signaling plays a pivotal role in a variety of pathological processes such as cancer, metastasis, angiogenesis and fibrosis. Therefore, TGF-β inhibitors should be promising therapeutic agents for the suppression of cancer progression and metastasis as well as fibrotic disorders. In a screening program of natural compounds from fungi inhibiting the TGF-β dependent expression of a reporter gene in HepG2 cells, we found that the fungal lactones (S)-curvularin, dehydrocurvularin, oxacyclododecindione and galiellalactone inhibited the binding of the activated Smad2/3 transcription factors to the DNA and antagonized the cellular effects of TGF-β including reporter gene activation and expression of TGF-β induced genes in HepG2 and MDA-MB-231 cells. The most active compound oxacyclododecindione inhibited TGF-β dependent reporter activity with IC50-values of 190-217 nM. In an in vitro angiogenesis assay, the fungal lactones strongly decreased the formation of capillary-like tubules of MDA-MB-231 cells on Matrigel.
authors.affiliation: Institute of Biotechnology and Drug Research (IBWF e.V.), Erwin-Schrödinger-Str. 56, D-67663 Kaiserslautern, Germany.
authors.forename: Kristina
authors.initials: K
authors.lastname: Rudolph
authors.forename: Annegret
authors.initials: A
authors.lastname: Serwe
authors.forename: Gerhard
authors.initials: G
authors.lastname: Erkel
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000187:drug effects; D024202:Electrophoretic Mobility Shift Assay; D017930:Genes, Reporter / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D007783:Lactones / Q000494:pharmacology*; D047028:Macrocyclic Compounds / Q000494:pharmacology*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D051899:Smad2 Protein / Q000187:drug effects / Q000378:metabolism; D051900:Smad3 Protein / Q000187:drug effects / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015025:Zearalenone / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D004268:DNA-Binding Proteins; D007783:Lactones; D047028:Macrocyclic Compounds; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; C416043:galiellalactone; C532274:oxacyclododecindione; C013914:dehydrocurvularin; D015025:Zearalenone; C013455:curvularin