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

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

Author information

1
Institute of Biotechnology and Drug Research (IBWF e.V.), Erwin-Schrödinger-Str. 56, D-67663 Kaiserslautern, Germany.

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.

PMID:
23134667
DOI:
10.1016/j.cyto.2012.10.011
[Indexed for MEDLINE]

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