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

Ko-Long Lin1, Chorng-Chih Huang, Jin-Shiung Cheng

  • 1Department of Rehabilitation, Kaohsiung Veterans General Hospital, 813 Kaohsiung, Taiwan.

Toxicology in Vitro : an International Journal Published in Association with BIBRA
|July 28, 2009
PubMed

Insights

Ketoconazole triggers apoptosis and reduces viability in MG63 osteosarcoma cells by activating JNK phosphorylation, independent of calcium levels. This antifungal drug

Area of Science:

  • Oncology
  • Cell Biology
  • Pharmacology

Background:

  • Osteosarcoma is a primary bone malignancy with limited treatment options.
  • Understanding the mechanisms of cell death induction is crucial for developing novel therapeutic strategies.

Purpose of the Study:

  • To investigate the effects of ketoconazole on MG63 osteosarcoma cells.
  • To elucidate the role of mitogen-activated protein kinases (MAPKs) and calcium signaling in ketoconazole-induced cell death.

Main Methods:

  • MG63 cells were treated with varying concentrations of ketoconazole.
  • Cell viability was assessed using propidium iodide staining.
  • Apoptosis was evaluated by caspase-3 activation.
  • MAPK phosphorylation (ERK, JNK, p38) was analyzed by immunoblotting.
  • Intracellular calcium levels were measured using a calcium indicator and BAPTA chelation.

Main Results:

  • Ketoconazole decreased cell viability and induced apoptosis in a dose-dependent manner.
  • Ketoconazole treatment led to the phosphorylation of ERK and JNK, but not p38.
  • JNK inhibition partially reversed ketoconazole-induced cell death, while ERK inhibition had no effect.
  • Ketoconazole increased intracellular calcium, but this was not essential for its cytotoxic effects.
  • Apoptosis was mediated by JNK phosphorylation in a calcium-independent pathway.

Conclusions:

  • Ketoconazole induces apoptosis and cell death in MG63 osteosarcoma cells.
  • The cytotoxic effect is primarily mediated by JNK phosphorylation, independent of intracellular calcium increases.
  • Ketoconazole's mechanism involves JNK activation, suggesting potential therapeutic avenues in osteosarcoma treatment.

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