Inhibition of TGF-β signaling by the fungal lactones (S)-curvularin, dehydrocurvularin, oxacyclododecindione and galiellalactone

Cytokine. 2013 Jan;61(1):285-96. doi: 10.1016/j.cyto.2012.10.011. Epub 2012 Nov 5.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • DNA-Binding Proteins / drug effects
  • Electrophoretic Mobility Shift Assay
  • Genes, Reporter / drug effects
  • Hep G2 Cells
  • Humans
  • Lactones / pharmacology*
  • Macrocyclic Compounds / pharmacology*
  • Neovascularization, Physiologic / drug effects
  • Signal Transduction / drug effects
  • Smad2 Protein / drug effects
  • Smad2 Protein / metabolism
  • Smad3 Protein / drug effects
  • Smad3 Protein / metabolism
  • Transforming Growth Factor beta / antagonists & inhibitors*
  • Transforming Growth Factor beta / metabolism
  • Zearalenone / analogs & derivatives*
  • Zearalenone / pharmacology


  • DNA-Binding Proteins
  • Lactones
  • Macrocyclic Compounds
  • SMAD2 protein, human
  • SMAD3 protein, human
  • Smad2 Protein
  • Smad3 Protein
  • Transforming Growth Factor beta
  • galiellalactone
  • oxacyclododecindione
  • dehydrocurvularin
  • Zearalenone
  • curvularin