The tumor inhibitor and antiangiogenic agent withaferin A targets the intermediate filament protein vimentin

Chem Biol. 2007 Jun;14(6):623-34. doi: 10.1016/j.chembiol.2007.04.010.


The natural product withaferin A (WFA) exhibits antitumor and antiangiogenesis activity in vivo, which results from this drug's potent growth inhibitory activities. Here, we show that WFA binds to the intermediate filament (IF) protein, vimentin, by covalently modifying its cysteine residue, which is present in the highly conserved alpha-helical coiled coil 2B domain. WFA induces vimentin filaments to aggregate in vitro, an activity manifested in vivo as punctate cytoplasmic aggregates that colocalize vimentin and F-actin. WFA's potent dominant-negative effect on F-actin requires vimentin expression and induces apoptosis. Finally, we show that WFA-induced inhibition of capillary growth in a mouse model of corneal neovascularization is compromised in vimentin-deficient mice. These findings identify WFA as a chemical genetic probe of IF functions, and illuminate a potential molecular target for withanolide-based therapeutics for treating angioproliferative and malignant diseases.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / chemistry
  • Angiogenesis Inhibitors / pharmacology
  • Angiogenesis Inhibitors / therapeutic use
  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Apoptosis / drug effects
  • Binding Sites
  • Blotting, Western
  • Cell Line
  • Corneal Neovascularization / drug therapy
  • Electrophoresis, Gel, Two-Dimensional
  • Ergosterol / analogs & derivatives*
  • Ergosterol / chemistry
  • Ergosterol / pharmacology
  • Ergosterol / therapeutic use
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Flow Cytometry
  • Humans
  • Mice
  • Mice, Knockout
  • Models, Molecular
  • Molecular Structure
  • Protein Binding
  • Vimentin / genetics
  • Vimentin / metabolism*
  • Withanolides


  • Angiogenesis Inhibitors
  • Antineoplastic Agents
  • Vimentin
  • Withanolides
  • withaferin A
  • Ergosterol