Abstract 259: Antitumor activities of yuanhuadine, a daphnane diterpene from Daphne genkwa, via epidermal growth factor receptor signaling in non-small cell lung cancer cells

Abstract

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). The ligand-induced epidermal growth factor receptor (EGFR) and c-Met signalings were also inhibited by 1. The oral administration of 1 (0.5 mg/kg body weight, daily) for 14 days inhibited tumor growth in athymic xenograft nude mouse model bearing human lung A549 cells significantly, 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 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 259. doi:1538-7445.AM2012-259