Web of Science: 80 cites, Scopus: 84 cites, Google Scholar: cites,
Histone deacetylase inhibitors promote glioma cell death by G2 checkpoint abrogation leading to mitotic catastrophe
Cornago, M. (Institut de Recerca Biomèdica de Lleida)
Garcia-Alberich, C. (Institut de Recerca Biomèdica de Lleida)
Blasco-Angulo, N. (Institut de Recerca Biomèdica de Lleida)
Vall-llaura, N. (Institut de Recerca Biomèdica de Lleida)
Nager, M. (Institut de Recerca Biomèdica de Lleida)
Herreros, J. (Institut de Recerca Biomèdica de Lleida)
Comella i Carnicé, Joan Xavier 1963- (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Sanchis, D.. (Institut de Recerca Biomèdica de Lleida)
Llovera, Marta (Institut de Recerca Biomèdica de Lleida)
Universitat Autònoma de Barcelona

Data: 2014
Resum: Glioblastoma multiforme is resistant to conventional anti-tumoral treatments due to its infiltrative nature and capability of relapse; therefore, research efforts focus on characterizing gliomagenesis and identifying molecular targets useful on therapy. New therapeutic strategies are being tested in patients, such as Histone deacetylase inhibitors (HDACi) either alone or in combination with other therapies. Here two HDACi included in clinical trials have been tested, suberanilohydroxamic acid (SAHA) and valproic acid (VPA), to characterize their effects on glioma cell growth in vitro and to determine the molecular changes that promote cancer cell death. We found that both HDACi reduce glioma cell viability, proliferation and clonogenicity. They have multiple effects, such as inducing the production of reactive oxygen species (ROS) and activating the mitochondrial apoptotic pathway, nevertheless cell death is not prevented by the pan-caspase inhibitor Q-VD-OPh. Importantly, we found that HDACi alter cell cycle progression by decreasing the expression of G2 checkpoint kinases Wee1 and checkpoint kinase 1 (Chk1). In addition, HDACi reduce the expression of proteins involved in DNA repair (Rad51), mitotic spindle formation (TPX2) and chromosome segregation (Survivin) in glioma cells and in human glioblastoma multiforme primary cultures. Therefore, HDACi treatment causes glioma cell entry into mitosis before DNA damage could be repaired and to the formation of an aberrant mitotic spindle that results in glioma cell death through mitotic catastrophe-induced apoptosis.
Ajuts: Instituto de Salud Carlos III ISCIII-PI080790
Agència de Gestió d'Ajuts Universitaris i de Recerca 2009/SGR-346
Drets: Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original. Creative Commons
Llengua: Anglès
Document: Article ; recerca ; Versió publicada
Publicat a: Cell death and disease, Vol. 5 (october 2014) , p. e1435, ISSN 2041-4889

DOI: 10.1038/cddis.2014.412
PMID: 25275596

13 p, 3.7 MB

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