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

Abstract

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.

Ferroptosis: Final destination for cancer?

“…The stemness of CSCs can be verified by detecting the expression of typical surface markers (CD133, CD44, CD24, CD38) and pluripotency factors (Sox2, Oct4, Nanog) and by their capacity to form spheres. William's team found a new compound that can inhibit system Xc ‐ to induce ferroptosis in cancer stem cells . Different from general cancer cells, increased iron content in CSCs is a key feature in several types of tumours.…”

Targeting Long Chain Acyl-CoA Synthetases for Cancer Therapy

“…Altogether, these results suggest that ACSL4 inhibition is a viable therapeutic approach to prevent ferroptosis-related diseases. Interestingly, triggering ferroptosis could represent a therapeutic strategy for the treatment of many neoplasias, alone or in combination with chemoterapeutic agents [99]. Thus, it could be speculated that ACSL4 may represent a double-edged sword target, since both enhances cell proliferation and invasion and sensitizes cancer cells to ferroptotic stimuli.…”

The Role of Intra-Tumoral Heterogeneity and Its Clinical Relevance in Epithelial Ovarian Cancer Recurrence and Metastasis

“…Overcoming recurrence will therefore partially depend upon novel therapeutic approaches that are able to reverse chemoresistance and target CSCs. For instance, a recent study in breast cancer determined that a novel agent that activated reactive oxygen species-dependent ferroptosis was more effective against breast cancer stem-like cells [100]. Two additional studies in HGSC found that delivery of small interfering RNA against TWIST1, a transcription factor implicated in chemoresistance and EMT, sensitized ovarian tumors to platinum drugs in an in vivo model [101], and anti-tumor efficacy was further improved if nanoparticle carriers were coated in hyaluronic acid and therefore targeted to CD44+ cells [102].…”