Research

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

Annick Mühlethaler-Mottet¹ , Roland Meier² , Marjorie Flahaut¹ , Katia Balmas Bourloud¹ , Katya Nardou¹ , Jean-Marc Joseph³ and Nicole Gross¹

¹  Paediatric Oncology Research, Paediatric Department, University Hospital CHUV, CH-1011 Lausanne, Switzerland

²  Life Sciences Division, Lawrence Berkeley National Laboratory, University of California, Berkeley, CA 94720, USA

³  Paediatric Surgery, Paediatric Department, University Hospital CHUV, CH-1011 Lausanne, Switzerland

author email corresponding author email

Molecular Cancer 2008, 7:55doi:10.1186/1476-4598-7-55

Published:	12 June 2008

Abstract

Background

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.