Hesperetin Induces Apoptosis of Human Gastric Adenocarcinoma Cells

초록

Objectives: Hesperetin is a major flavanone component contained in citrus fruits. It has been reported to possess anti-oxidant and anti-cancer effects. The objective of this study was to identify the anti-gastric cancer effect of hesperetin and investigate the mechanism involved in such effect. Methods: To confirm the effect of hesperetin on the survival of AGS gastric cancer cell lines, WST cell viability assay, Annexin V and propidium iodide (PI) staining, and Western blot were performed. To identify the mechanisms involved, protein expressions were confirmed by performing Western blot using cell lysate obtained after treatment of hesperetin at different concentrations and times in AGS cells. Results: Decreased cell viability by hesperetin was due to the induction of apoptosis mediated by activation of caspases 3, 7, 8, and 9. Expression levels of X-linked inhibitor of apoptosis protein (XIAP) and survivin were reduced by hesperetin. In addition, the ratio of B-cell lymphoma-2 (Bcl-2) to Bcl-2-associated X protein (Bax) was increased by hesperetin. Furthermore, activities of focal adhesion kinase (FAK), phosphatidylinositol-3-kinase (PI3K), and serine/threonine kinase (AKT) were decreased while that of AMP-activated protein kinase (AMPK) was increased by hesperetin, thereby confirming that the activation of mammalian target of rapamycin (mTOR) was inhibited. Additionally, hesperetin inhibited the activation of signal transducer and activator of transcription 3 (STAT3) and its transcription factor c-Myc. Conclusion: These results indicate that hesperetin can inhibit gastric cancer cells by inducing apoptosis, which could be mediated by activation of caspases and inhibition of proteins related to mitochondrial apoptosis, FAK, PI3K, AKT, AMPK, mTOR pathway, and STAT3 signaling.

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