Modulatory profiling identifies mechanisms of small molecule-induced cell death

Proc Natl Acad Sci U S A. 2011 Sep 27;108(39):E771-80. doi: 10.1073/pnas.1106149108. Epub 2011 Sep 6.


Cell death is a complex process that plays a vital role in development, homeostasis, and disease. Our understanding of and ability to control cell death is impeded by an incomplete characterization of the full range of cell death processes that occur in mammalian systems, especially in response to exogenous perturbations. We present here a general approach to address this problem, which we call modulatory profiling. Modulatory profiles are composed of the changes in potency and efficacy of lethal compounds produced by a second cell death-modulating agent in human cell lines. We show that compounds with the same characterized mechanism of action have similar modulatory profiles. Furthermore, clustering of modulatory profiles revealed relationships not evident when clustering lethal compounds based on gene expression profiles alone. Finally, modulatory profiling of compounds correctly predicted three previously uncharacterized compounds to be microtubule-destabilizing agents, classified numerous compounds that act nonspecifically, and identified compounds that cause cell death through a mechanism that is morphologically and biochemically distinct from previously established ones.

Publication types

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

MeSH terms

  • Cell Death / drug effects*
  • Cell Death / physiology
  • Cell Line
  • Humans
  • Microtubules / drug effects
  • Signal Transduction
  • bcl-2 Homologous Antagonist-Killer Protein
  • bcl-2-Associated X Protein / physiology


  • BAK1 protein, human
  • bcl-2 Homologous Antagonist-Killer Protein
  • bcl-2-Associated X Protein