Small-molecule anticancer agents kill cancer cells by harnessing reactive oxygen species in an iron-dependent manner

Abstract

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 in an iron-dependent manner. Results of the preliminary studies are consistent with the recently described cell death mechanism ferroptosis. Studies are in progress to confirm ferroptosis as the cell death mechanism and to identify the specific molecular targets of these small molecule anticancer agents.

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

“…1) which had a similar activity profile as the parent compound 1 . Further investigations revealed that compound 4 , its epimer 5 , the racemate 6 , and the oxime analogue 7 selectively killed cancer cells by a nonapoptotic mechanism of action mediated by ROS in an iron-dependent manner, consistent with ferroptosis 11 . Here we further characterize the mechanism of cell death, and identify a potential mechanism of action.…”

“…Initial studies with compound 4 suggested that cytotoxicity towards a number of cancer cells was due to induction of ferrotposis. For example, killing of NCI-H522 cells by compound 4 was blocked by iron chelators ciclopirox olamine 11 , hydroxyurea 11 and deferoxamine (Fig. 2A).…”

“…2B and ref. 11 ). Sensitivity was enhanced by adding ferric citrate, suggesting that iron plays a role in cell death mechanism 11 .…”

“…11 ). Sensitivity was enhanced by adding ferric citrate, suggesting that iron plays a role in cell death mechanism 11 . Further, free radical scavengers, trolox and butylated hydroxyanisole blocked the death of NCI-H522 cells induced by 4 , suggesting that compound 4 relies on ROS for cytotoxic activity 11 .…”

“…We recently reported that in the course of developing open chain epothilone analogues, we discovered the molecule 1 (Fig. 1) that killed selected cancer cells by a non-apoptotic mechanism of action 11 . Its analogues, compounds 2 and 3 without a terminal alkyne group were not active.…”