Hesperidin enhances the antiproliferative and apoptotic effects of oxaliplatin in AGS gastric cancer cells through modulation of apoptosis-related proteins

Abstract

Gastric cancer remains a leading cause of cancer-related mortality worldwide, with poor prognosis and high rates of resistance to platinum-based chemotherapy. Hesperidin (HES), a citrus-derived flavanone glycoside, has demonstrated anticancer properties, but its potential as an adjuvant to oxaliplatin (OXA) in gastric cancer has not been fully explored. The cytotoxic effects of HES, OXA, and their combination were evaluated in AGS gastric cancer cells and HUVEC normal endothelial cells using WST-1 assays and morphological analysis. Wound healing assay was applied to assess antimigratory activity. Apoptotic mechanisms were investigated by ELISA-based quantification of caspase-3, -8, and -9, and Western blot analysis of Bax, Bcl-2, p53, and Survivin. HES inhibited the proliferation of AGS cells in a dose- and time-dependent manner (with IC50 values of 170.4 µM at 24 h and 92.06 µM at 48 h) and showed limited cytotoxicity in HUVEC cells. OXA exerted stronger antiproliferative activity (IC50= 24.16 µM at 24 h), and its combination with HES produced a greater inhibition of proliferation and migration (p <0.0001). Combination treatment significantly increased caspase activation: caspase-3, caspase-8, and caspase-9 levels increased by approximately 2.7-fold, 3.0-fold, and 2.8-fold, respectively (p <0.0001). Furthermore, HES + OXA treatment downregulated Bcl-2 and Survivin (approximately 4.5- and 5-fold, respectively) while increasing Bax and p53 expression (approximately 9- and 5-fold, respectively), indicating significant (p <0.0001) activation of both intrinsic and extrinsic apoptotic pathways. These findings suggest that HES may augment OXA-induced apoptosis and migration inhibition in gastric cancer cells.

Keywords

• Gastric cancer
• Hesperidin
• Oxaliplatin
• Apoptosis

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