Antioxidative Effects of Curcumin on Erastin-Induced Ferroptosis Through GPX4 Signalling

Background/Objectives: Pancreatic cancer is a common gastrointestinal cancer with high risk of mortality. Currently, the therapeutic strategies for pancreatic cancers are surgery, chemotherapy, and radiotherapy, none of which are effective treatments. Ferroptosis is a new form of cell death that is iron (Fe)-dependent and characterized by lipid peroxidation, which is a new approach for treatment of pancreatic cancer. Therefore, this study was dedicated to investigating the effect of erastin and Ras-selective lethal small molecule 3 (RLS3) as ferroptosis inducers as well as focusing on the antioxidant effects of two natural products, curcumin and (−)-epigallocatechin-3-gallate (EGCG), against ferroptosis. Methods: PANC1 cells were treated with 20 μmol/L curcumin or EGCG and then exposed to 20 μmol/L erastin. Cell viability was detected by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide (MTT) assay, Reactive Oxygen Species (ROS) were measured by dihydrodichlorofluorescein (H2DCF) cell-permeant probe, Fe levels were determined by inductively coupled plasma mass spectrometry (ICP-MS), and glutathione (GSH), lipid peroxidation, Western blot, and mRNA were assayed with commercially available kits. Results: Curcumin and EGCG enhanced cell viability in erastin-treated PANC1 cells in a dose-and time-dependent manner. Erastin-treated PANC1 cells exhibited the elevated levels of GSH depletion, ROS productions, and lipid peroxidation while curcumin reversed the erastin-induced ferroptotic effects. The treatment of erastin-induced PANC1 cells with curcumin increased the GPX4 mRNA gene and protein levels. Also, curcumin decreased the FTH1 mRNA gene levels as a strong Fe chelator. Conclusions: In conclusion, this study shows that erastin can be potentially a therapeutic strategy for treatment of cancer cells. Additionally, curcumin might play an antioxidant role at the specific concentrations, potentially mitigating ferroptosis in cells.