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.
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.


OBJECTIVE
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.


METHODS
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.
College of Pharmacy, Nanjing University of Chinese Medicines, Xianlin Avenue No. 138, 210023 Nanjing, China. Electronic address: wxzatnj@sina.com.
Xin-Zhi
XZ
Wang
College of Pharmacy, Nanjing University of Chinese Medicines, Xianlin Avenue No. 138, 210023 Nanjing, China.
Ying
Y
Cheng
College of Pharmacy, Nanjing University of Chinese Medicines, Xianlin Avenue No. 138, 210023 Nanjing, China.
Hao
H
Wu
College of Pharmacy, Nanjing University of Chinese Medicines, Xianlin Avenue No. 138, 210023 Nanjing, China.
Na
N
Li
College of Pharmacy, Nanjing University of Chinese Medicines, Xianlin Avenue No. 138, 210023 Nanjing, China.
Rui
R
Liu
College of Pharmacy, Nanjing University of Chinese Medicines, Xianlin Avenue No. 138, 210023 Nanjing, China.
Xiao-Lin
XL
Yang
College of Pharmacy, Nanjing University of Chinese Medicines, Xianlin Avenue No. 138, 210023 Nanjing, China.
Yun-Ying
YY
Qiu
College of Pharmacy, Nanjing University of Chinese Medicines, Xianlin Avenue No. 138, 210023 Nanjing, China.
Hong-Mei
HM
Wen
Department of Natural Medicinal Chemistry, China Pharmaceutical University, Tongjia Lane No. 24, 210009, Nanjing, China.
Jing-Yu
JY
Liang
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D052117:Benzodioxoles / Q000494:pharmacology*; D002277:Carcinoma / Q000188:drug therapy / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000187:drug effects*; D009368:Neoplasm Transplantation; D051058:Oncogene Protein v-akt / Q000187:drug effects*; D017239:Paclitaxel / Q000627:therapeutic use; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects*; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000473:pathology
D000972:Antineoplastic Agents, Phytogenic; D052117:Benzodioxoles; C545363:peperomin E; D019869:Phosphatidylinositol 3-Kinases; D051058:Oncogene Protein v-akt; D017239:Paclitaxel
Apoptosis; Gastric carcinoma cells; Mitochondria; PI3K/Akt, Subcutaneous tumor model; Peperomin E