Inhibition of TGF-β signaling, vasculogenic mimicry and proinflammatory gene expression by isoxanthohumol

Invest New Drugs. 2012 Jun;30(3):898-915. doi: 10.1007/s10637-011-9643-3. Epub 2011 Feb 22.


TGF-β is a multifunctional cytokine that regulates cell proliferation, differentiation, apoptosis and extracellular matrix production. Deregulation of TGF-β production or signaling has been associated with a variety of pathological processes such as cancer, metastasis, angiogenesis and fibrosis. Therefore, TGF-β signaling has emerged as an attractive target for the development of new cancer therapeutics. 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 flavone isoxanthohumol 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. In an in vitro angiogenesis assay, isoxanthohumol (56 μM) strongly decreased the formation of capillary-like tubules of MDA-MB-231 cells on Matrigel. In addition, we found that isoxanthohumol blocked IFN-γ, IL-4 and IL-6 dependent Jak/Stat signaling and strongly inhibited the induction of pro-inflammatory genes in MonoMac6 cells at the transcriptional level after LPS/TPA treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cytokines / genetics
  • Cytokines / metabolism
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Janus Kinases / metabolism
  • NF-kappa B / genetics
  • RNA, Messenger / metabolism
  • STAT Transcription Factors / genetics
  • STAT Transcription Factors / metabolism
  • Transforming Growth Factor beta / antagonists & inhibitors*
  • Xanthones / pharmacology*


  • Antineoplastic Agents
  • Cytokines
  • NF-kappa B
  • RNA, Messenger
  • STAT Transcription Factors
  • Transforming Growth Factor beta
  • Xanthones
  • isoxanthohumol
  • Janus Kinases