Harnessing Ferroptosis in PDAC: Curcumin Enhances RSL3-Induced Lipid Peroxidation and Cytotoxicity

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer that remains without an effective treatment and characterized by its resistance to conventional therapies and evasion of programmed cell death pathways.This study investigates a combinatorial therapeutic approach using curcumin, a natural ingredient with antioxidant properties, and RSL3, a ferroptosis inducer that inhibits GPX4 of the ASCL4 pathway.Mouse PDAC cells were treated with curcumin, RSL3, and Ferrostatin-1 both individually and in combination to determine their half-maximal inhibitory concentrations (IC50) and evaluate synergistic effects on cell viability.The IC50 of curcumin was found to be about 50 M meanwhile for RSL3 it was about 0.5 M.Dose-response assays revealed a possible enhanced cytotoxicity in combinatorial treatments compared to monotherapy, particularly with curcumin and RSL3.ROS staining using DCFH-DA was performed to visualize oxidative stress to physically see the ASCL4 pathway, although fixed-cell imaging introduced an unexpected result where a green-fluorescent ROS stain turned into a red nucleolus stain.Despite limitations including single-trial IC50 determinations and possible pipetting errors, our results suggest that curcumin primes PDAC cells for ferroptotic death enhancing RSL3 efficacy.These findings highlight the therapeutic potential of natural-drug combinations to treat PDAC.