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Research Articles: Therapeutics, Targets, and Development

Combined effects of retinoic acid and histone deacetylase inhibitors on human neuroblastoma SH-SY5Y cells

Instituto de Investigaciones Biomédicas "Alberto Sols," Consejo Superior de Investigaciones Cientificas-Universidad Autonoma de Madrid, Madrid, Spain

Requests for reprints: Ana Aranda, Arturo Duperier 4, 28029 Madrid, Spain. Phone: 34-91-5854453; Fax: 34-91-5854401. E-mail: aaranda{at}iib.uam.es

Abstract

All-trans retinoic acid (RA) causes differentiation of neuroblastoma cells, and retinoids have been used in clinical trials in children with advanced neuroblastoma. Combination of RA with histone deacetylase inhibitors (HDACi) could result in improved antitumorigenic activity. We have examined the effect of the HDACi trichostatin A (TSA), sodium butyrate, and suberoylanilide hydroxamic acid (SAHA), alone and in combination with RA in human neuroblastoma SH-SY5Y cells. At concentrations that cause sustained increase of histone H3 acetylation, HDACi produced extensive apoptotic cell death as shown by flow cytometry analysis and induction of poly(ADP-ribose) polymerase proteolysis. HDACi inhibited SH-SY5Y cell growth at a much larger extent than RA. This compound did not cause apoptosis and did not further increase HDACi-mediated cell death. In contrast, both types of drugs cooperated to inhibit cell growth, although synergistic effects were not found. In surviving cells, HDACi repressed cyclin D1 expression and increased the cyclin kinase inhibitors (CKI) p21^Waf1/Cip1 and p27^Kip1. Cyclin D1 was not affected by RA, but this retinoid also increased CKI levels. Induction of p21^Waf1/Cip1 and p27^Kip1 by HDACi was further enhanced in the presence of RA. This effect seems to be at least partially due to transcriptional stimulation of CKI gene expression because both types of drugs cooperated to increase CKI mRNA levels and to activate the CKI promoters in transient transfection assays. These results show the strong antitumorigenic effects of HDACi in neuroblastoma cells and reinforce the idea that combination therapy could be useful to inhibit tumor growth. [Mol Cancer Ther 2007;6(4):1425–32]

Grant support: BFU2004 03465 from Ministerio de Ciencia y Tecnología, RD06/0020/0036 from Fondo de Investigaciones Sanitarias, and by Fundación La Caixa.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 10/ 9/06; revised 12/15/06; accepted 2/21/07.

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