title: Bufalin induces apoptosis in vitro and has Antitumor activity against human lung cancer xenografts in vivo.
abstract: Bufalin has been shown to be effective against a variety of cancer cells, but its role in lung cancer has never been studied in an animal model. In this study, we evaluated bufalin effects in a human lung cancer cell line NCI-H460 both in vitro and in vivo. Bufalin caused significant cytotoxicity in NCI-H460 cells at a concentration as low as 1 μM. DNA condensation was observed in bufalin-treated cells in a dose-dependent manner. Mitochondrial membrane potential (ΔΨm) was reduced and reactive oxygen species (ROS) were increased in bufalin-treated NCI-H460 cells. Levels of several proapoptotic proteins such as Fas, Fas-ligand, cytochrome c, apoptosis protease activating factor-1, endonuclease G, caspase-3 and caspase-9 were increased after bufalin treatment. At the same time, anti-apoptotic B-cell lymphoma 2 protein levels were reduced. Bufalin decreased glucose regulated protein-78 gene expression but increased growth arrest- and DNA damage-inducible 153 gene expression. Bufalin injected intraperitoneally in a dose-dependent manner reduced tumor size in BALB/C nu/nu mice implanted with NCI-H460 cells. Bufalin injection did not produce significant drug-related toxicity in experimental animals except at a high dose (0.4 mg kg-1). In conclusion, low concentrations of bufalin can induce apoptosis in the human lung cancer cell line NCI-H460 in vitro. Bufalin also reduced tumor size in mice injected with NCI-H460 cells without significant drug-related toxicity. These results indicate that bufalin may have potential to be developed as an agent for treating human non-small cell lung cancer. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1305-1317, 2017.
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, 500, Taiwan.
authors.forename: Shin-Hwar
authors.initials: SH
authors.lastname: Wu
authors.affiliation: Terry Fox Cancer Research Laboratory, Department of Medical Research, China Medical University Hospital, Taichung, 404, Taiwan.
authors.forename: Da-Tian
authors.initials: DT
authors.lastname: Bau
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: College of Chinese Medicine, School of Post-Baccalaureate Chinese Medicine, China Medical University, Taichung, 404, Taiwan.
authors.forename: Kung-Wen
authors.initials: KW
authors.lastname: Lu
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: School of Pharmacy, China Medical University, Taichung, 40402, Taiwan.
authors.forename: Jin-Cherng
authors.initials: JC
authors.lastname: Lien
authors.affiliation: Institute of Clinical Medical Science, China Medical University, Taichung, 404, Taiwan.
authors.forename: Yang-Ching
authors.initials: YC
authors.lastname: Ko
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 Radiology, China Medical University Hospital, Taichung, 404, Taiwan.|School of Chinese Medicine, China Medical University, Taichung, 404, Taiwan.
authors.forename: Su-Tso
authors.initials: ST
authors.lastname: Yang
authors.affiliation: Department of Physiology, China Medical University, Taichun, 404, Taiwan.
authors.forename: Yi-Ping
authors.initials: YP
authors.lastname: Huang
authors.affiliation: Department of Biological Science and Technology, China Medical University, Taichung, 404, Taiwan.|Department of Biotechnology, Asia University, Taichung, 404, Taiwan.
authors.forename: Jing-Gung
authors.initials: JG
authors.lastname: Chung
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002018:Bufanolides / Q000627:therapeutic use / Q000633:toxicity*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D002843:Chromatin / Q000187:drug effects / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects; D004195:Disease Models, Animal; D000091342:Endoplasmic Reticulum Chaperone BiP; D053222:Fas Ligand Protein / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D017382:Reactive Oxygen Species / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D002018:Bufanolides; D002843:Chromatin; D000091342:Endoplasmic Reticulum Chaperone BiP; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D006360:Heat-Shock Proteins; D017382:Reactive Oxygen Species; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; C022777:bufalin
keywords: animal models; apoptosis; bufalin; lung neoplasm