Abstract
Menin‑mixed‑lineage leukemia (MLL) inhibitors have potential for use as therapeutic agents for MLL‑rearranged leukemia. They are also effective against solid cancers, such as breast cancer. The present study demonstrated that menin‑MLL inhibitors, such as MI‑463, unexpectedly induced the ferroptotic cell death of several cancer cell lines. MI‑463 at a double‑digit nM concentration markedly decreased the viable number of OVCAR‑8 ovarian cancer cells for 3 days. Ferrostatin‑1 (a ferroptosis inhibitor) almost completely abrogated the MI‑463‑induced decrease in viable cell numbers. Furthermore, the cancer cell‑killing activity was inhibited by N‑acetylcysteine [a scavenger of reactive oxygen species (ROS)], deferoxamine (DFO, an iron chelator), PD146176 (a specific inhibitor of arachidonate 15‑lipoxygenase), idebenone (a membrane‑permeable analog of CoQ10) and oleic acid [a monounsaturated fatty acid and one of the end products of stearoyl‑CoA desaturase 1 (SCD1)], whereas Z‑VAD‑FMK (an apoptosis inhibitor) had a negligible effect on cell death. It was also found that MI‑463 in combination with auranofin (a thioredoxin reductase inhibitor) synergistically increased cancer the death of breast, ovarian, pancreatic and lung cancer cell lines (88%, 14/16 cell lines). The synergistic induction of cell death was abrogated by ferroptosis inhibitor and DFO. Inhibitors of SCD1, similar to MI‑463, also enhanced cancer cell death synergistically with auranofin, while inhibitors of SCD1 and MI‑463 did not additively induce cell death. Treatment with zinc protoporphyrin‑9, a specific inhibitor of heme oxygenase‑1 (HO‑1), markedly attenuated the cell death induced by MI‑463 plus auranofin. On the whole, these results suggest that the MI‑463‑induced decrease in cell viability may be at least partly associated with the inhibition of SCD1 activity. In addition, the potent induction of HO‑1 contributed to the synergistic effects of MI‑463 plus auranofin. Therefore, menin‑MLL inhibitors, such as MI‑463, in combination with auranofin represent an effective therapeutic approach for several types of cancer via the induction of ferroptosis.