The authors declare that there is no conflict of interest.
Original Research Article
Parthenolide induces caspase-independent and AIF-mediated cell death in human osteosarcoma and melanoma cells†
Article first published online: 28 JAN 2013
Copyright © 2012 Wiley Periodicals, Inc.
Journal of Cellular Physiology
Volume 228, Issue 5, pages 952–967, May 2013
How to Cite
D'Anneo, A., Carlisi, D., Lauricella, M., Emanuele, S., Di Fiore, R., Vento, R. and Tesoriere, G. (2013), Parthenolide induces caspase-independent and AIF-mediated cell death in human osteosarcoma and melanoma cells. J. Cell. Physiol., 228: 952–967. doi: 10.1002/jcp.24131
- Issue published online: 28 JAN 2013
- Article first published online: 28 JAN 2013
- Accepted manuscript online: 11 JUN 2012 12:26PM EST
- Manuscript Accepted: 1 JUN 2012
- Manuscript Received: 20 JAN 2012
- “Innovative Research Project,” 2007, University of Palermo, Italy
- Ministero dell'Istruzione, dell'Università e della Ricerca” (MIUR)
The mechanism of the cytotoxic effect exerted by parthenolide on tumor cells is not clearly defined today. This article shows that parthenolide stimulates in human osteosarcoma MG63 and melanoma SK-MEL-28 cells a mechanism of cell death, which is not prevented by z-VAD-fmk and other caspase inhibitors. In particular treatment with parthenolide rapidly stimulated (1–2 h) reactive oxygen species (ROS) generation by inducing activation of extracellular signal-regulated kinase 1/2 (ERK 1/2) and NADPH oxidase. This event caused depletion of thiol groups and glutathione, NF-κB inhibition, c-Jun N-terminal kinase (JNK) activation, cell detachment from the matrix, and cellular shrinkage. The increase of ROS generation together with the mitochondrial accumulation of Ca2+ also favored dissipation of Δψm, which seemed primarily determined by permeability transition pore opening, since Δψm loss was partially prevented by the inhibitor cyclosporin A. Staining with Hoechst 33342 revealed in most cells, at 3–5 h of treatment, chromatin condensation, and fragmentation, while only few cells were propidium iodide (PI)-positive. In addition, at this stage apoptosis inducing factor (AIF) translocated to the nucleus and co-localized with areas of condensed chromatin. Prolonging the treatment (5–15 h) ATP content declined while PI-positive cells strongly augmented, denouncing the increase of necrotic effects. All these effects were prevented by N-acetylcysteine, while caspase inhibitors were ineffective. We suggest that AIF exerts a crucial role in parthenolide action. In accordance, down-regulation of AIF markedly inhibited parthenolide effect on the production of cells with apoptotic or necrotic signs. Taken together our results demonstrate that parthenolide causes in the two cell lines a caspase-independent cell death, which is mediated by AIF. J. Cell. Physiol. © 2012 Wiley Periodicals, Inc.