Synthetic lethal screening identifies compounds activating iron-dependent, nonapoptotic cell death in oncogenic-RAS-harboring cancer cells

Chem Biol. 2008 Mar;15(3):234-45. doi: 10.1016/j.chembiol.2008.02.010.


We screened small molecules to identify two compounds, which we named RSL3 and RSL5, that have increased lethality in the presence of oncogenic RAS. Counter screening with biologically active compounds defined aspects of the mechanism of action for RSL3 and RSL5, such as a nonapoptotic, MEK-dependent, and iron-dependent oxidative cell death. Erastin, a previously reported compound with RAS-selective lethality, showed similar properties. RNA interference experiments targeting voltage-dependent anion channel 3 (VDAC3), a target of erastin, demonstrated that RSL5 is a scaffold that acts through VDACs to activate the observed pathway. RSL3 activated a similar death mechanism but in a VDAC-independent manner. We found that cells transformed with oncogenic RAS have increased iron content relative to their normal cell counterparts through upregulation of transferrin receptor 1 and downregulation of ferritin heavy chain 1 and ferritin light chain.

Publication types

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

MeSH terms

  • Apoptosis
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Drug Evaluation, Preclinical
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Iron / metabolism*
  • Mutation
  • Neoplasms / drug therapy
  • Neoplasms / metabolism*
  • Neoplasms / pathology*
  • Piperazines / pharmacology
  • Proto-Oncogene Proteins p21(ras) / genetics*
  • Proto-Oncogene Proteins p21(ras) / metabolism*
  • Small Molecule Libraries / pharmacology*
  • Substrate Specificity
  • Voltage-Dependent Anion Channels / metabolism


  • Piperazines
  • Small Molecule Libraries
  • Voltage-Dependent Anion Channels
  • erastin
  • Iron
  • Proto-Oncogene Proteins p21(ras)