%0 Journal Article
%T Complex molecular mechanisms cooperate to mediate histone deacetylase inhibitors anti-tumour activity in neuroblastoma cells
%A Annick M¨¹hlethaler-Mottet
%A Roland Meier
%A Marjorie Flahaut
%A Katia Bourloud
%A Katya Nardou
%A Jean-Marc Joseph
%A Nicole Gross
%J Molecular Cancer
%D 2008
%I BioMed Central
%R 10.1186/1476-4598-7-55
%X We show here that the HDACi Sodium Butyrate (NaB), suberoylanilide hydroxamic acid (SAHA) and Trichostatin A (TSA) strongly reduce NB cells viability. The anti-tumour activity of these HDACi involved the induction of cell cycle arrest in the G2/M phase, followed by the activation of the intrinsic apoptotic pathway, via the activation of the caspases cascade. Moreover, HDACi mediated the activation of the pro-apoptotic proteins Bid and BimEL and the inactivation of the anti-apoptotic proteins XIAP, Bcl-xL, RIP and survivin, that further enhanced the apoptotic signal. Interestingly, the activity of these apoptosis regulators was modulated by several different mechanisms, either by caspases dependent proteolytic cleavage or by degradation via the proteasome pathway. In addition, HDACi strongly impaired the hypoxia-induced secretion of VEGF by NB cells.HDACi are therefore interesting new anti-tumour agents for targeting highly malignant tumours such as NB, as these agents display a strong toxicity toward aggressive NB cells and they may possibly reduce angiogenesis by decreasing VEGF production by NB cells.Histone deacetylase inhibitors (HDACi) are promising new anti-tumour agents due to their low toxicity toward normal cells and their ability to inhibit tumour growth in vivo. HDACi are currently under clinical trials and have activity in hematologic malignancies and solid tumours at doses that are well tolerated by patients [1-3].HDACs regulate the expression and the activity of many proteins involved in cancer initiation and progression. HDACs affect gene expression by deacetylation of histones and transcription factors, and also deacetylate numerous other cellular proteins involved in cell growth, cell migration, apoptosis and differentiation [2,4,5]. Thus HDACi mediate their anti-tumour action by transcription-dependent and transcription-independent mechanisms. HDACi induce diverse responses in tumour cells, such as differentiation, cell cycle arrest, cell death by
%U http://www.molecular-cancer.com/content/7/1/55