title: Bufalin Inhibits NCI-H460 Human Lung Cancer Cell Metastasis In Vitro by Inhibiting MAPKs, MMPs, and NF-κB Pathways.
abstract: Bufalin, a component of Chan Su (a traditional Chinese medicine), has been known to have antitumor effects for thousands of years. In this study, we investigated its anti-metastasis effects on NCI-H460 lung cancer cells. Under sub-lethal concentrations (from 25 up to 100 nM), bufalin significantly inhibits the invasion and migration nature of NCI-H460 cells that were measured by Matrigel Cell Migration Assay and Invasion System. Bufalin also suppressed the enzymatic activity of matrix metalloproteinase (MMP)-9, which was examined by gelatin zymography methods. Western blotting revealed that bufalin depressed several key metastasis-related proteins, such as NF-κB, MMP-2, MMP-9, protein kinase C (PKC), phosphatidylinositol 3-kinase (PI3-K), phosphorylated Akt, growth factor receptor-bound protein 2 (GRB2), phosphorylated extracellular signal-regulated kinase (ERK), phosphorylated p38, and phosphorylated c-Jun NH2-terminal kinase (JNK). As evidenced by immunostaining and the electrophoretic mobility shift assay (EMSA), bufalin induced not only a decreased cytoplasmic NF-κB production, but also decreased its nuclear translocation. Several metastasis-related genes, including Rho-associated (Rho A), coiled-coil-containing protein kinase 1 (ROCK1), and focal adhesion kinase (FAK), were down-regulated after bufalin treatment. In conclusion, bufalin is effective in inhibiting the metastatic nature of NCI-H460 cells in low, sub-lethal concentrations. Such an effect involves many mechanisms including MMPs, mitogen-activated protein kinases (MAPKs) and NF-κB systems. Bufalin has a potential to evolve into an anti-metastasis drug for human lung cancer in the future.
authors.affiliation: Institute of Clinical Medical Science, China Medical University, Taichung 404, Taiwan.|Division of Critical Care Medicine, Department of Medicine, Changhua Christian Hospital, Changhua 505, Taiwan.
authors.forename: Shin-Hwar
authors.initials: SH
authors.lastname: Wu
authors.affiliation: Department of Biological Science and Technology, China Medical University, Taichung 404, Taiwan.
authors.forename: Yung-Ting
authors.initials: YT
authors.lastname: Hsiao
authors.affiliation: Department of Chinese Medicine Resources, China Medical University, Taichung 404, Taiwan.
authors.forename: Chao-Lin
authors.initials: CL
authors.lastname: Kuo
authors.affiliation: School of Dentistry, China Medical University, Taichung 404, Taiwan.
authors.forename: Fu-Shun
authors.initials: FS
authors.lastname: Yu
authors.affiliation: Department of Biological Science and Technology, China Medical University, Taichung 404, Taiwan.
authors.forename: Shu-Chun
authors.initials: SC
authors.lastname: Hsu
authors.affiliation: School of Pharmacy, China Medical University, Taichung 404, Taiwan.
authors.forename: Ping-Ping
authors.initials: PP
authors.lastname: Wu
authors.affiliation: Department of Medicinal Botany and Health Applications, Da-Yeh University, Changhua 515, Taiwan.
authors.forename: Jaw-Chyun
authors.initials: JC
authors.lastname: Chen
authors.affiliation: Department of Internal Medicine, China Medical University Hospital, Taichung 404, Taiwan.
authors.forename: Te-Chun
authors.initials: TC
authors.lastname: Hsia
authors.affiliation: Department of Chinese Medicine Resources, China Medical University, Taichung 404, Taiwan.
authors.forename: Hsin-Chung
authors.initials: HC
authors.lastname: Liu
authors.affiliation: Department of Internal Medicine, China Medical University, Taichung 404, Taiwan.|Department of Internal Medicine, China Medical University Hospital, Taichung 404, Taiwan.
authors.forename: Wu-Huei
authors.initials: WH
authors.lastname: Hsu
authors.affiliation: Department of Chinese Medicine Resources, China Medical University, Taichung 404, Taiwan.|Department of Biotechnology, Asia University, Taichung 413, Taiwan.
authors.forename: Jing-Gung
authors.initials: JG
authors.lastname: Chung
mesh_terms: D002018:Bufanolides / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D002018:Bufanolides; D016328:NF-kappa B; D048049:Extracellular Signal-Regulated MAP Kinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; C022777:bufalin
keywords: Bufalin; MAPKs; MMPs; NCI-H460 Cells; NF-κB