L-securinine induces apoptosis in the human promyelocytic leukemia cell line HL-60 and influences the expression of genes involved in the PI3K/AKT/mTOR signaling pathway.

Abstract

The Securinega alkaloids are a class of natural products isolated from plants of the Euphorbiaceae family. L-securinine induces apoptosis in the human promyelocytic leukemia cell line HL-60 indicating its potential as an efficient natural antitumor drug with low toxicity. The aim of the present study was to investigate the apoptotic effects of L-securinine on HL-60 cells and to explore its potential underlying molecular mechanism(s) as an antitumor agent. HL-60 cells were cultured with L-securinine. The proliferation and changes in cell morphology were evaluated by cell counting Kit-8 (CCK-8) assay and electron microscopy, respectively. Induction of apoptosis and cell cycle progression were investigated by flow cytometry. The PI3K/AKT/mTOR pathway gene expression was measured by quantitative PCR (qPCR). L-securinine decreased the viability of HL-60 cells in a dose- and time-dependent manner, with IC50 values at 24, 48 and 72 h post-treatment of 47.88, 23.85 and 18.87 µmol/l, respectively. Numerous apoptotic bodies were observed in the HL-60 cells treated with 25 µmol/l L-securinine for 48 h. L-securinine at 12.5, 25 and 50 µmol/l increased the rate of apoptosis in HL-60 cells, and G1/S phase progression was retarded. Furthermore, L-securinine induced downregulation of PI3K, AKT and mTOR gene expression and upregulation of PTEN gene expression in a dose-dependent manner. In conclusion, L-securinine induces apoptosis and inhibition of cell cycle progression in HL-60 cells by modulation of the PI3K/AKT/mTOR pathway gene expression. These observations indicate the potential of L-securinine as an antitumor agent.

• Authors: Shuwen Han, Gang Zhang, Maidong Li, Dongyun Chen, Ying Wang, Wencai Ye, Zhaoning Ji
• Journal: Oncology reports (Oncol Rep) Vol. 31 Issue 5 Pg. 2245-51 (May 2014) ISSN: 1791-2431 [Electronic] Greece
• PMID: 24676995 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Phytogenic
• Azepines
• Heterocyclic Compounds, Bridged-Ring
• Lactones
• Piperidines
• MTOR protein, human
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• PTEN Phosphohydrolase
• PTEN protein, human
• securinine

Topics

• Antineoplastic Agents, Phytogenic (pharmacology)
• Apoptosis (drug effects)
• Azepines (pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Gene Expression
• HL-60 Cells
• Heterocyclic Compounds, Bridged-Ring (pharmacology)
• Humans
• Lactones (pharmacology)
• Leukemia, Promyelocytic, Acute (drug therapy)
• MAP Kinase Signaling System (genetics)
• PTEN Phosphohydrolase (biosynthesis)
• Phosphatidylinositol 3-Kinases (biosynthesis, genetics)
• Piperidines (pharmacology)
• Proto-Oncogene Proteins c-akt (biosynthesis, genetics)
• S Phase Cell Cycle Checkpoints (drug effects)
• TOR Serine-Threonine Kinases (biosynthesis, genetics)