Complex molecular mechanisms cooperate to mediate histone deacetylase inhibitors anti-tumour activity in neuroblastoma cells

Mühlethaler-Mottet Annick, Meier Roland, Flahaut Marjorie, Bourloud Katia, Nardou Katya, Joseph Jean-Marc, Gross, Gross Nicole

Description

Histone deacetylase inhibitors (HDACi) are a new class of promising anti-tumour agent inhibiting cell proliferation and survival in tumour cells with very low toxicity toward normal cells. Neuroblastoma (NB) is the second most common solid tumour in children still associated with poor outcome in higher stages and, thus NB strongly requires novel treatment modalities. Results 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 Bim EL and the inactivation of the anti-apoptotic proteins XIAP, Bcl-x L , 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. Conclusion 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.

Informations

• Publié par: biomed
• Publié le: 01 janvier 2008
• Nombre de lectures: 4
• Langue: English
• Poids de l'ouvrage: 1 Mo

Extrait

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Bio Med Central

Research Open Access Complex molecular mechanisms cooperate to mediate histone deacetylase inhibitors anti-tumour activity in neuroblastoma cells Annick Mühlethaler-Mottet 1 , Roland Meier 2 , Marjorie Flahaut 1 , Katia Balmas Bourloud 1 , Katya Nardou 1 , Jean-Marc Joseph 3 and Nicole Gross* 1

Address: 1 Paediatric Oncology Research, Paediatric Department, Un iversity Hospital CHUV, CH -1011 Lausanne, Switzerland, 2 Life Sciences Division, Lawrence Berkeley National Laboratory, University of California, Berkeley, CA 94720, USA and 3 Paediatric Surgery, Paediatric Department, University Hospital CHUV, CH-1011 Lausanne, Switzerland Email: Annick Mühlethaler-Motte t - [e-mail]; Roland Meier - [e-mail]; Marjorie Flahaut - [e-mail]; Katia B almas Bourloud - Katia.Balm [e-mail]; Katya Nardou - [e-mail]; Je an-Marc Joseph - [e-mail] ; Nicole Gross* - [e-mail] * Corresponding author

Molecular Cancer

Published: 12 June 2008 Received: 21 December 2007 Molecular Cancer 2008, 7 :55 doi:10.1186/1476-4598-7-55  Accepted: 12 June 2008 This article is available from: http:/ /www.molecular-cancer.com/content/7/1/55 © 2008 Mühlethaler-Mottet et a l; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons. org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the orig inal work is properly cited.

Abstract Background:Histone deacetylase inhibitors (HDACi) ar e a new class of promising anti-tumour agent inhibiting cell proliferatio n and survival in tumour cells wit h very low toxicity toward normal cells. Neuroblastoma (NB) is the second most co mmon solid tumour in children still associated with poor outcome in higher stag es and, thus NB strongly requ ires novel treatment modalities. Results: We show here that the HDACi Sodium Butyr ate (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 cycl e arrest in the G2/M phase, followed by the activation of the intrinsic apopto tic pathway, via the activation of the caspases cascade. Moreover, HDACi mediated the ac im and the inactivation of tivation of th e pro-apoptotic proteins Bid and B EL the anti-apoptotic proteins XIAP, Bcl-x L , 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 prot eolytic cleavage or by degradation via the proteasome pathway. In additi on, HDACi strongly impaired the hypoxia-induced secretion of VEGF by NB cells. Conclusion: HDACi are therefore interesting new anti-tumour agents for targeting highly malignant tumours such as NB, as these agents disp lay a strong toxicity towa rd aggressive NB cells and they may possibly reduce angiogenesis by decreasing VEGF production by NB cells.