Obtusilactone A and (-)-sesamin induce apoptosis in human lung cancer cells by inhibiting mitochondrial Lon protease and activating DNA damage checkpoints.

Abstract

Several compounds from Cinnamomum kotoense show anticancer activities. However, the detailed mechanisms of most compounds from C. kotoense remain unknown. In this study, we investigated the anticancer activity of obtusilactone A (OA) and (-)-sesamin in lung cancer. Our results show that human Lon is upregulated in non-small-cell lung cancer (NSCLC) cell lines, and downregulation of Lon triggers caspase-3 mediated apoptosis. Through enzyme-based screening, we identified two small-molecule compounds, obtusilactone A (OA) and (-)-sesamin from C. kotoense, as potent Lon protease inhibitors. Obtusilactone A and (-)-sesamin interact with Ser855 and Lys898 residues in the active site of the Lon protease according to molecular docking analysis. Thus, we suggest that cancer cytotoxicity of the compounds is partly due to the inhibitory effects on Lon protease. In addition, the compounds are able to cause DNA double-strand breaks and activate checkpoints. Treatment with OA and (-)-sesamin induced p53-independent DNA damage responses in NSCLC cells, including G(1) /S checkpoint activation and apoptosis, as evidenced by phosphorylation of checkpoint proteins (H2AX, Nbs1, and Chk2), caspase-3 cleavage, and sub-G(1) accumulation. In conclusion, OA and (-)-sesamin act as both inhibitors of human mitochondrial Lon protease and DNA damage agents to activate the DNA damage checkpoints as well induce apoptosis in NSCLC cells. These dual functions open a bright avenue to develop more selective chemotherapy agents to overcome chemoresistance and sensitize cancer cells to other chemotherapeutics.

• Authors: Hui-Min Wang, Kuo-Chen Cheng, Cheng-Jung Lin, Shu-Wei Hsu, Wei-Cheng Fang, Tai-Feng Hsu, Chien-Chih Chiu, Hsueh-Wei Chang, Chun-Hua Hsu, Alan Yueh-Luen Lee
• Journal: Cancer science (Cancer Sci) Vol. 101 Issue 12 Pg. 2612-20 (Dec 2010) ISSN: 1349-7006 [Electronic] England
• PMID: 21077998 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2010 Japanese Cancer Association.

Chemical References

• Antineoplastic Agents
• Dioxoles
• Lignans
• obtusilactone A
• Protease La
• sesamin

Topics

• Amino Acid Sequence
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Blotting, Western
• Carcinoma, Non-Small-Cell Lung (genetics, metabolism)
• Cell Line, Tumor
• Cell Separation
• Comet Assay
• DNA Damage
• Dioxoles (chemistry, pharmacology)
• Flow Cytometry
• Humans
• Lignans (chemistry, pharmacology)
• Lung Neoplasms (genetics, metabolism)
• Mitochondria (drug effects, enzymology)
• Molecular Sequence Data
• Protease La (chemistry, drug effects, metabolism)
• Protein Structure, Quaternary
• Signal Transduction (drug effects)