Activity tracking isolation of Gelsemium elegans alkaloids and evaluation of their antihuman gastric cancer activity in vivo

Abstract

• Forty-two Gelsemium elegans alkaloids (GEAs) were isolated in an antineoplastic activity tracking method and structure identified. • GEA-9 induced mitochondria-mediated apoptosis by increasing Bax/Bcl-2 and p53/MDM2 expression ratio in MKN-45 cells. • GEA-9 inhibited the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway. • GEA-9 inhibited the growth of MKN-45 cells xenograft tumors. Gastric cancer (GC) is a fatal form of tumor that has no effective therapeutic agents. In this study, an anticancer tracking method was applied to ioslate Gelsemium elegans alkaloids (GEAs) in vitro . GEA-9 (11-methoxy- N 1 -demethoxygelsemamide) exhibited the highest antiproliferative activity in MKN-45 cells and induced mitochondrion-mediated apoptosis, It decreased the mitochondrial potential and increased the Bax/Bcl-2 and p53/MDM2 expression ratio. It also induced cell cycle arrest in MKN-45 cells by regulating the cyclin expression. It Inhibited the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway and the growth of MKN-45 cell xenograft tumors, which were associated with light chain 3-II activation and mTOR inhibition. In summary, we first demonstrated the antineoplastic effect of GEA-9 in vitro and in vivo . We also elucidated that the underlying antineoplastic mechanisms of GEA-9 involved the crosstalk between apoptosis and autophagy by inhibiting of the PI3K/Akt/mTOR pathway. This study might provide a rationale for future clinical applications of GEAs as a chemotherapeutic agents for GC. GEAs were isolated in a bio-assay guided method, and GEA-9 involve cross talk between apoptosis and autophagy via inhibition of the PI3K/Akt/mTOR pathway in gastric cancer MKN-45 cells.