Harnessing Ferroptosis in PDAC: Curcumin Enhances RSL3-Induced Lipid Peroxidation and Cytotoxicity
DOI:
https://doi.org/10.58445/rars.2928Keywords:
PDAC, Ferroptosis, Cancer Therapy, Cancer Biology, Pancreatic Cancer, Cancer Treatment, Drug Combination, Curcumin, RSL-3, Ferrostatin-1Abstract
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 µM meanwhile for RSL3 it was about 0.5 µM. 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.
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