New curcumin derivative induces ferroptosis in MCF-7 cells through activating SLC7A11/GPX4 axis.

Previous experiments have revealed that curcumin exerts potential antitumor effect by inducing apoptosis and ferroptosis of tumor cells. However, its low solubility and bioavailability, as well as fast metabolism limit its clinical use. The structural modification of curcumin is beneficial for the discovery of potential candidate drugs for cancer treatment. Here, three new series of curcumin derivatives including 25 compounds were synthesized at active sites on benzene ring and β-diketone moiety. Further antiproliferative activities against five cancer cell lines (Hela, A549, HepG2, MCF-7 and HT-29) in vitro showed that compound 4a-4e displayed remarkable anti-tumor effect against A549, HepG2, MCF-7 and HT-29. Of them, compound 4d is particularly prominent against MCF-7, with IC50 of 1.39 μM. Preliminary mechanism found that compound 4d could trigger ferrous ions and ROS accumulation, increase MDA level in MCF-7 cells, while significantly down-regulate GPX4 level in dose-dependent manner. Western Blot results discovered that compound 4d decreased the ratio of SLC7A11 to GAPDH and GPX4 to β-actin. Docking results indicated that compound 4d had good binding affinity to the active site of GPX4 (PDB ID: 7u4n and 7u4k). In conclusion, compound 4d may be potential anti-tumor agent, which induces ferroptosis in MCF-7 cells through activating SLC7A11/GPX4 axis.