title: Ketoconazole-induced JNK phosphorylation and subsequent cell death via apoptosis in human osteosarcoma cells.
abstract: This study examined the effect of ketoconazole on viability, apoptosis, mitogen-activated protein kinases (MAPKs) and Ca(2+) levels in MG63 osteosarcoma cells. Ketoconazole at 20-200 microM decreased cell viability via apoptosis as demonstrated by propidium iodide staining and activation of caspase-3. Immunoblotting suggested that ketoconazole induced phosphorylation of ERK and JNK, but not p38, MAPKs. Ketoconazole-induced cell death and apoptosis were partially reversed by the selective JNK inhibitor SP600125, but not by the selective ERK inhibitor PD98059, suggesting that ketoconazole's cytotoxic action was via JNK, but not via ERK and p38 MAPKs. Ketoconazole at a concentration of 100 microM induced [Ca(2+)](i) increases. Chelation of intracellular Ca(2+) with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA) totally inhibited ketoconazole-induced [Ca(2+)](i) increases without reversing ketoconazole-induced cell death. Collectively, in MG63 cells, ketoconazole induced cell death and apoptosis via evoking JNK phosphorylation in a Ca(2+)-independent manner.
authors.affiliation: Department of Rehabilitation, Kaohsiung Veterans General Hospital, 813 Kaohsiung, Taiwan.
authors.forename: Ko-Long
authors.initials: KL
authors.lastname: Lin
authors.forename: Chorng-Chih
authors.initials: CC
authors.lastname: Huang
authors.forename: Jin-Shiung
authors.initials: JS
authors.lastname: Cheng
authors.forename: Jeng-Yu
authors.initials: JY
authors.lastname: Tsai
authors.forename: Yih-Chau
authors.initials: YC
authors.lastname: Lu
authors.forename: Hong-Tai
authors.initials: HT
authors.lastname: Chang
authors.forename: Chung-Ren
authors.initials: CR
authors.lastname: Jan
mesh_terms: D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D001859:Bone Neoplasms / Q000201:enzymology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003603:Cytotoxins / Q000633:toxicity*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D007654:Ketoconazole / Q000633:toxicity*; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism; D012516:Osteosarcoma / Q000201:enzymology*; D010766:Phosphorylation / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D003603:Cytotoxins; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D007654:Ketoconazole