Radiosensitizing effects of Withaferin A in gastric cancer cells via autophagy Inhibition and mitochondrial disruption.

Gastric cancer is highly lethal due to late-stage diagnosis and resistance to standard treatments like radiotherapy. Enhancing radiosensitivity in gastric cancer cells could improve treatment outcomes. Withaferin A (WA), a bioactive compound from Withania somnifera, has anticancer effects and can modulate cellular processes like autophagy and mitochondrial function. This study investigates WA's role in enhancing radiosensitivity by targeting apoptosis, autophagy, and mitochondrial function in SGC-7901 gastric cancer cells. In both in vitro and in vivo models, combined WA and radiation (IR) treatment significantly inhibited tumor growth, as evidenced by reduced tumor size in xenografts. Mechanistically, this combination promoted apoptosis, with increased levels of cleaved caspase-3 and PARP, indicating enhanced cell death. WA altered autophagic dynamics by activating autophagy and blocking autophagic flux, shown by LC3II accumulation and SQSTM1/p62 buildup. Moreover, the combined treatment disrupted mitochondrial function, leading to decreased ATP production, reduced respiratory capacity, and increased proton leakage, which contributed to cellular stress. These findings suggest that WA may serve as a radiosensitizer to enhance radiotherapy efficacy in gastric cancer, highlighting its therapeutic potential and advocating for further exploration of phytocompounds in cancer treatment.