Sulfasalazine an Inhibitor of System xC - (Cystine/glutamate Antiporter), Combined With Recombinant Methioninase, Inhibits Both Cancer and Normal Cells, Suggesting Lack of Cancer Selectivity of Cysteine Restriction.

BACKGROUND/AIM: Sulfasalazine (SSZ), an inhibitor of xCT/system xC -, blocks cystine uptake and depletes intracellular glutathione, leading to ferroptotic cell death. Recombinant methioninase (rMETase) targets methionine addiction of cancer inhibits cancer growth, and enhances the efficacy of chemotherapy. Targeting the cysteine and methionine metabolism pathways together may effect synergistic efficacy. The present study determined whether SSZ combined with rMETase results in cancer-selective efficacy compared with normal cells.

MATERIALS AND

METHODS

The half-maximal inhibitory concentrations (IC50) of SSZ and rMETase were each determined on HCT116 human colon-cancer cells and Hs-27 human normal fibroblasts in vitro. Viability of HCT116 and Hs-27 cells treated with SSZ alone, rMETase alone, or the combination of SSZ and rMETase was determined with the WST-8 viability reagent.

RESULTS

SSZ had similar IC50 values on HCT116 cancer cells and Hs-27 normal fibroblasts (1.25 mM vs. 1.11 mM, respectively). In contrast, rMETase had higher efficacy on HCT116 colon-cancer cells (IC50=0.33 U/ml) than on Hs-27 fibroblasts (IC50=0.55 U/ml), indicating greater sensitivity of cancer cells. The combination of SSZ and rMETase significantly reduced cell viability compared with untreated control, SSZ alone, and rMETase alone, on both HCT116 and Hs-27 cells (each comparison, all p<0.05), demonstrating that the enhanced efficacy of SSZ under methionine restriction is not cancer-selective.

CONCLUSION

SSZ shows comparable growth inhibition in cancer and normal cells and displays enhanced efficacy in combination with rMETase on both cell types. These findings suggest that cysteine restriction, unlike methionine restriction, is not a cancer-specific vulnerability.