Small-Molecule Ferroptotic Agents with Potential to Selectively Target Cancer Stem Cells

Sci Rep. 2019 Apr 11;9(1):5926. doi: 10.1038/s41598-019-42251-5.


Effective management of advanced cancer requires systemic treatment including small molecules that target unique features of aggressive tumor cells. At the same time, tumors are heterogeneous and current evidence suggests that a subpopulation of tumor cells, called tumor initiating or cancer stem cells, are responsible for metastatic dissemination, tumor relapse and possibly drug resistance. Classical apoptotic drugs are less effective against this critical subpopulation. In the course of generating a library of open-chain epothilones, we discovered a new class of small molecule anticancer agents that has no effect on tubulin but instead kills selected cancer cell lines by harnessing reactive oxygen species to induce ferroptosis. Interestingly, we find that drug sensitivity is highest in tumor cells with a mesenchymal phenotype. Furthermore, these compounds showed enhanced toxicity towards mesenchymal breast cancer populations with cancer stem cell properties in vitro. In summary, we have identified a new class of small molecule ferroptotic agents that warrant further investigation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Proliferation
  • Ferroptosis*
  • Humans
  • Mesoderm / drug effects
  • Mesoderm / pathology
  • Neoplasms / drug therapy*
  • Neoplasms / pathology
  • Neoplastic Stem Cells / drug effects*
  • Neoplastic Stem Cells / pathology
  • Reactive Oxygen Species / metabolism*
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Tumor Cells, Cultured


  • Antineoplastic Agents
  • Reactive Oxygen Species
  • Small Molecule Libraries