Published online 4 February 2010
(Haematologica 2010, 10.3324/haematol.2009.013870)
Copyright © 2010 by Ferrata Storti Foundation
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Article

Vorinostat interferes with the signaling transduction pathway of T cell receptor and synergizes with PI3K inhibitors in cutaneous T-cell lymphoma

Magdalena B. Wozniak1, Raquel Villuendas1, James R. Bischoff2, Carmen Blanco-Aparicio2, Juan F. Martínez Leal2, Paloma de La Cueva1, Mª Elena Rodriguez1, Beatriz Herreros1, Daniel Martin-Perez1, Maria I. Longo3, Marta Herrera4, Miguel Á. Piris1, Pablo L Ortiz-Romero4

1 Molecular Pathology Program, Spanish National Cancer Centre, Madrid, Spain
2 Experimental Therapuetics Program, National Cancer Centre, Madrid, Spain
3 Dermatology Department, Hospital Gregorio Marañon, Madrid, Spain
4 Dermatology Department, Hospital 12 de Octubre, Madrid, Spain

Correspondence: Dr. Miguel A Piris, Spanish National Cancer Centre (CNIO) Melchor Fernández Almagro 3, Madrid 28029, Spain Phone: international +34.91.2246900. Fax: international +34.91.2246923. E-mail: mapiris{at}cnio.es, Dr. Pablo L Ortiz-Romero, Servicio de Dermatología, Hospital 12 de Octubre Av. De Cordoba s/n, 28041 Madrid, Spain Phone: international +34.91.3908302. Fax: international +34.91.4608377. E-mail: portiz.hdoc{at}salud.madrid.org

ABSTRACT

Background: Vorinostat [Suberoylanilide hydroxamic acid (SAHA)], an inhibitor of class I and II histone deacetylases (HDAC), has been approved for the treatment of cutaneous T-cell lymphoma (CTCL). In spite of emerging information on vorinostat effect on many cancer types, there is still little knowledge on mechanism of action, essential for the proper use in combination therapy. Herein, we investigate the alterations in gene expression profile (GEP) in CTCL cells treated with vorinostat over time. Subsequently, we have evaluated inhibitors of PI3K, PIM and HSP90 as potential combination agents in the treatment of CTCL.

Design and Methods: The genes significantly up- or down-regulated by vorinostat over different time periods (2-fold change, FDR corrected P-value<0.05) were selected using short-time series expression miner (STEM). Cell viability was examined in vitro in CTCL cells through measuring intracellular ATP content. Drug interactions were analysed by the combination index method with Calcusyn software.

Results: The functional analysis suggests that vorinostat modifies signaling of T cell receptor, MAPK, and JAK-STAT pathways. The phosphorylation studies of ZAP70 (Tyr319, Tyr493) and its downstream target AKT (Ser473) revealed that vorinostat inhibits phosphorylation of these kinases. Combination of vorinostat with PI3K inhibitors resulted in synergy while cytotoxic antagonism was observed when combining vorinostat with HSP90 inhibitor in CTCL.

Conclusions: These results demonstrate the potential targets of SAHA, underlining the importance of TCR signaling inhibition following vorinostat treatment. Additionaly, we show that combination therapies involving HDACi and inhibitors of PI3K can be potentially efficacious for the treatment of CTCL.

Key words: Vorinostat, gene expression, cutaneous T-cell lymphoma, synergy, HDAC inhibitors.