Resveratrol Enhances Sulfasalazine-induced Ferroptosis by Promoting Iron Ion Accumulation and Lipid Peroxidation in Cancer Cells

Abstract

Background/aim: Sulfasalazine (SSZ) has traditionally been used as an immunomodulator; however, recent studies have highlighted its potential as a novel anticancer agent due to its ability to induce ferroptosis, an iron-dependent form of cell death. Resveratrol (RSV), a plant-derived bioactive compound commonly marketed as a dietary supplement, is known for its antioxidant and metabolic regulatory properties. This study aimed to investigate whether the combination of SSZ and RSV enhances antitumor activity and to elucidate their effects on ferroptosis.

Materials and methods: Human melanoma cell lines expressing CD44 variant 9 and xCT, a transporter for SSZ, were used in this study. Cell viability was assessed using metabolic assays and flow cytometry. The accumulation of intracellular iron ions and lipid peroxides in cancer cells was analyzed via fluorescence microscopy.

Results: The combination of SSZ and RSV significantly reduced the viability of melanoma cell lines. Treatment with SSZ led to an increase in reactive oxygen species (ROS) levels and a decrease in reduced glutathione (GSH) levels, both of which were further exacerbated by RSV. Furthermore, the combination of SSZ and RSV enhanced the accumulation of divalent iron ions and lipid peroxides within the mitochondria of cancer cells.

Conclusion: SSZ and RSV exhibit a synergistic antitumor effect against cancer cells and enhance iron-dependent cell death, ferroptosis.

Keywords: Sulfasalazine; ferroptosis; lipid peroxidation; resveratrol; xCT.