Induction of apoptosis by ethanol extract of sapodilla leaf in HGT-1 cells involved caspase-independent signal transduction pathway and activation of Nrf2/HO-1

Gastric cancer has become one of the most common cancers globally. Sapodilla or known as <i>Manilkara zapota</i> (L.) P. Royen, has been traditionally applied for cough, cold, and diarrhea. The detailed mechanisms in modulating sapodilla leaf 70% ethanol extract against HGT-1 human gastric cancer cell line have yet to be fully studied. Apoptosis induction was evaluated using an Annexin V-FITC/PI staining kit with flow cytometry. Caspase-3 and -8 expression were determined by colorimetric analysis. To explore the molecular mechanisms of action of the 70% ethanol extract of sapodilla leaves in HGT-1 cells, quantitative real-time PCR (qPCR) was performed. Overall analyses demonstrated that sapodilla leaf 70% ethanol extract was cytotoxic and suppressed the growth of HGT-1 cells. The 70% ethanol extract of sapodilla leaves significantly suppressed the proliferation of HGT-1 cells. Moreover, it enhanced the expression of nuclear factor E2-related factor 2 (<i>Nrf2</i>) and heme oxygenase-1 (<i>HO-1</i>), while concurrently suppressing the transcriptional activities of nuclear factor-kappa B (<i>NF-κB</i>) and inducible nitric oxide synthase (<i>iNOS</i>). Results indicate that sapodilla leaf 70% ethanol extract has an anti-gastric cancer effect via modulation of multiple signaling pathways. Sapodilla leaf 70% ethanol extract demonstrates promising potential as an anti-gastric cancer agent.