The natural secolignan peperomin E induces apoptosis of human gastric carcinoma cells via the mitochondrial and PI3K/Akt signaling pathways in vitro and in vivo.

ABSTRACT

BACKGROUND: Peperomin E (PepE) is a type of secolignan that is a major component of the plant Peperomia dindygulensis. It has been shown to exert anticancer effects in various cancer cell lines; however, the effects of PepE on human gastric cancer remain unexplored. PURPOSE: The aim of this study was to investigate the effectiveness of PepE as a treatment of gastric cancer and to identify the underlying mechanisms of its anticancer activity. STUDY DESIGN: The efficacy of PepE was examined using human gastric carcinoma SGC-7901, BGC-823, MKN-45 cell lines and normal gastric epithelial GES-1 cell line as an in vitro model and SGC-7901 xenograft mice as an in vivo model. METHODS: Cell viability assays were used to examine the anticancer effect of 0-204.8µM concentrations of PepE in vitro. Additionally, flow cytometry and western blotting were used to elucidate the mechanism with a particular focus on apoptosis. SGC-7901 cells were injected into BALB/c mice, which were then treated with 5 or 15mg/kg/day dose of PepE. The in vivo activity of PepE was investigated by measuring tumors and conducting immunohistochemistry experiments. The safety of PepE was investigated by measuring blood biochemical parameters and conducting histopathological analysis. Taxol was used throughout as a positive control. RESULTS: The results showed that PepE exhibited antiproliferative effects against gastric cancer cells and induced their apoptosis in a dose dependent manner with lower toxicity against normal gastric epithelial cells. Mechanistic evaluations indicated that PepE induced apoptosis by reducing the mitochondrial membrane potential (MTP), inducing cytochrome C release from mitochondria, reducing the ratio of Bcl-2/Bax and Bcl-xl/Bad, increasing activation of caspase-3, and decreasing the levels of PI3K and pAkt. The apoptotic effect of PepE on SGC-7901 cells was partially blocked by an Akt activator SC79. PepE potently inhibited in vivo tumor growth with no obvious toxicity following subcutaneous inoculation of SGC-7901 cells in nude mice. CONCLUSIONS: These findings indicate that PepE can inhibit cell proliferation and induce apoptosis of gastric cancer cells through mitochondrial and PI3K/Akt signaling pathways with relative safety and may be a novel effective chemotherapeutic agent against gastric cancer.