Growth Inhibition of Human Lung Cancer Cells via Down-regulation of Epidermal Growth Factor Receptor Signaling by Yuanhuadine, a Daphnane Diterpene from Daphne genkwa
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- 作者：Ji-Young Hong ; Hwa-Jin Chung ; Hye-Jung Lee ; Hyen Joo Park ; Sang Kook Lee
- 刊名：Journal of Natural Products
- 出版年：2011
- 出版时间：October 28, 2011
- 年：2011
- 卷：74
- 期：10
- 页码：2102-2108
- 全文大小：935K
- 年卷期：v.74,no.10(October 28, 2011)
- ISSN：1520-6025
文摘
The growth inhibition and antitumor activities of yuanhuadine (1), a daphnane diterpenoid from the flowers of Daphne genkwa, were investigated in human lung cancer cells. Compound 1 exhibited a relatively selective growth inhibition against human lung cancer cells compared to other solid human cancer cell lines. The potent antiproliferative activity by 1 was associated with cell-cycle arrest and modulation of cell-signaling pathways. Cell-cycle arrest in the G0/G1 and G2/M phase was induced by 1 in A549 human non-small-cell lung cancer cells, and these events were correlated with the expression of checkpoint proteins including the up-regulation of p21 and down-regulation of cyclins, cyclin-dependent kinases 2 (CDK2) and 4 (CDK4), and c-Myc. Compound 1 also suppressed the expression of the Akt/mammalian target of rapamycin (mTOR) and its downstream effector molecules including p70 S6 kinase (p70S6K) and eukaryotic initiation factor 4E-binding protein 1 (4EBP1). Ligand-induced epidermal growth factor receptor (EGFR) and c-Met signaling were also inhibited by 1. The oral administration of 1 (0.5 mg/kg body weight, daily) for 14 days significantly inhibited tumor growth in athymic xenograft nude mouse model bearing human lung A549 cells, without any overt toxicity. Synergistic antiproliferative effects of compound 1 were also found in combination with the EGFR inhibitor gefitinib. Cell-cycle arrest and suppression of Akt/mTOR and EGFR signaling pathways might be plausible mechanisms of actions for the antiproliferative and antitumor activity of 1 in human non-small-cell lung cancer cells.