Ketoconazole-induced JNK phosphorylation and subsequent cell death via apoptosis in human osteosarcoma cells

Ko Long Lin, Chorng Chih Huang, Jin Shiung Cheng, Jeng Yu Tsai, Yih Chau Lu, Hong Tai Chang, Chung Ren Jan*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

17 Scopus citations

Abstract

This study examined the effect of ketoconazole on viability, apoptosis, mitogen-activated protein kinases (MAPKs) and Ca2+ levels in MG63 osteosarcoma cells. Ketoconazole at 20-200 μM 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 μM induced [Ca2+]i increases. Chelation of intracellular Ca2+ with 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid (BAPTA) totally inhibited ketoconazole-induced [Ca2+]i increases without reversing ketoconazole-induced cell death. Collectively, in MG63 cells, ketoconazole induced cell death and apoptosis via evoking JNK phosphorylation in a Ca2+-independent manner.

Original languageEnglish
Pages (from-to)1268-1276
Number of pages9
JournalToxicology in Vitro
Volume23
Issue number7
DOIs
StatePublished - 10 2009
Externally publishedYes

Keywords

  • Apoptosis
  • Ca
  • Ketoconazole
  • MAPKs
  • MG63 cells

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