Citrus limon Peel Extract Modulates Redox Enzymes and Induces Cytotoxicity in Human Gastric Cancer Cells

Gastric cancer remains a leading cause of cancer-related mortality worldwide. Citrus fruits are rich in polyphenols, exerting antioxidant and chemo-preventive activities, and lemon peel represents a valuable source of such bioactive compounds. Previous studies showed that <i>Citrus limon</i> peel extracts (LPE) inhibited the activity of some enzymes of the antioxidant system and reduced the interleukin-6-dependent invasiveness of gastric and colon cancer cells. In the present study, we have investigated the effects of LPE on the human gastric adenocarcinoma AGS and MKN-28 cells and on the activity of a crucial redox enzyme, catalase (CAT). Indeed, LPE significantly reduced the cell viability and clonogenic potential of the gastric cancer cells and induced morphological changes indicative of cytotoxicity. Moreover, LPE modulated the intracellular redox homeostasis by decreasing levels of the hydrogen peroxide-related reactive oxygen species (ROS) while increasing those of superoxide anions and decreasing levels of superoxide dismutases (SODs). Western blotting analysis revealed that LPE downregulated CAT, SOD-1, SOD-2, and monoamine oxidase A (MAO-A) protein expression level in both cell lines. Finally, the extract inhibited CAT activity in a dose-dependent manner (IC₅₀ = 0.008 ± 0.003 mg/mL; <i>K</i>_i = 0.012 ± 0.002 mg/mL). These findings indicate that LPE exerts cytotoxic and redox-modulating effects through the inhibition of antioxidant enzymes and the alteration of ROS balance. Therefore, the agro-industrial by-product LPE could be considered as a promising natural source of polyphenolic compounds with potential applications in the prevention and therapy of gastric cancer.