title: Growth inhibition of human lung cancer cells via down-regulation of epidermal growth factor receptor signaling by yuanhuadine, a daphnane diterpene from Daphne genkwa.
abstract: 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.
authors.affiliation: College of Pharmacy, Ewha Womans University, Seoul 120-750, Korea.
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Hong
authors.forename: Hwa-Jin
authors.initials: HJ
authors.lastname: Chung
authors.forename: Hye-Jung
authors.initials: HJ
authors.lastname: Lee
authors.forename: Hyen Joo
authors.initials: HJ
authors.lastname: Park
authors.forename: Sang Kook
authors.initials: SK
authors.lastname: Lee
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D002453:Cell Cycle / Q000187:drug effects; D032364:Daphne / Q000737:chemistry*; D004195:Disease Models, Animal; D004224:Diterpenes / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D066246:ErbB Receptors / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D035264:Flowers / Q000737:chemistry; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D013729:Terpenes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004224:Diterpenes; D013729:Terpenes; C039652:yuanhuadine; D066246:ErbB Receptors