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Parthenolide induces caspase-independent and AIF-mediated cell death in human osteosarcoma and melanoma cells.
MedLine Citation:
PMID:  22688575     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
The mechanism of the cytotoxic effect exerted by parthenolide on tumor cells is not clearly defined today. This paper 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) ROS generation by inducing activation of extracellular signal-regulated kinase1/2 (ERK1/2) and NADPH oxidase. This event caused depletion of thiol groups and glutathione, NF-κB inhibition, JNK activation, cell detachment from the matrix and cellular shrinkage. The increase of ROS generation together with the mitochondrial accumulation of Ca(2+) also favoured dissipation of ▵ψm, which seemed primarily determined by PTP opening, since ▵ψm loss was partially prevented by the inhibitor cyclosporin A. Staining with Hoechst 33342 revealed in most cells, at 3-5h of treatment, chromatin condensation and fragmentation, while only few cells were PI-positive. In addition, at this stage AIF translocated to the nucleus and co-localized with areas of condensed chromatin. Prolonging the treatment (5-15h) ATP content declined while PI-positive cells strongly augmented, denouncing the increase of necrotic effects. All these effects were prevented by NAC, 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.
Authors:
Antonella D'Anneo; Daniela Carlisi; Marianna Lauricella; Sonia Emanuele; Riccardo Di Fiore; Renza Vento; Giovanni Tesoriere
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-6-11
Journal Detail:
Title:  Journal of cellular physiology     Volume:  -     ISSN:  1097-4652     ISO Abbreviation:  -     Publication Date:  2012 Jun 
Date Detail:
Created Date:  2012-6-12     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0050222     Medline TA:  J Cell Physiol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2012 Wiley Periodicals, Inc.
Affiliation:
Dipartimento di Biomedicina Sperimentale e Neuroscienze Cliniche, Sezione di Scienze Biochimiche. Università degli Studi di Palermo, Italy.
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