Preclinical evidence for a beneficial impact of valproate on the response of small cell lung cancer to first-line chemotherapy Roland Hubaux a,b,e , Fabian Vandermeers a,b,e , Cecilia Crisanti c , Veena Kapoor c , Arse `ne Burny a , Ce ´line Mascaux d , Steven M. Albelda c , Luc Willems a, * a Cellular and Molecular Biology, Gembloux Agro-Bio Tech, Gembloux, Belgium b Interdisciplinary Cluster for Applied Genoproteomics (GIGA), University of Lie `ge (ULg), Belgium c Pulmonary, Allergy and Critical Care Division, University of Pennsylvania, School of Medicine, Philadelphia, PA, USA d Jules Bordet Institute, ULB, Brussels, Belgium ARTICLE INFO Article history: Received 3 February 2010 Received in revised form 16 March 2010 Accepted 19 March 2010 Available online 5 May 2010 Keywords: Small cell lung cancer Valproate HDAC Chemotherapy Mice ABSTRACT Prognosis of small cell lung carcinoma (SCLC) is particularly poor, less than 5% of patients with extensive stage being alive after two years. We hypothesized that SCLC chemotherapy could be improved by using histone deacetylase (HDAC) inhibitors based on their ability to interfere with lysine acetylation and to alter gene expression. The goal of this study was to evaluate the anticancer efficacy of a HDAC inhibitor (valproate: VPA) on SCLC cells in com- bination with the standard chemotherapeutic first-line regimen (cisplatin + etoposide). We show that VPA induces apoptosis of small cell lung cancer cell lines and improves efficacy of cisplatin combined with etoposide. Both mitochondrial and death receptor pathways are involved in VPA-induced apoptosis. As expected for an HDAC inhibitor, VPA hyperacety- lates histone H3. The mechanism of VPA pro-apoptotic activity involves induction of p21, inhibition of Bcl-xL, cleavage of Bid and phosphorylation of Erk and H2AX. In the presence of VPA, Bax is translocated from the cytoplasm to the mitochondria and cleaved in an 18 kDa isoform. Cytochrome c is released from the mitochondria into the cytosol. Tran- scriptomic analyses by microarray show that VPA modulates transcription of genes (Na + / K + ATPase, Bcl-xL) involved in chemoresistance to cisplatin and etoposide. Finally, the effi- cacy of VPA combined with cisplatin and etoposide is supported by preclinical models of SCLC cells engrafted into SCID mice. Together, these data demonstrate that VPA augments anticancer activity of cisplatin and etoposide, two components of the standard first-line chemotherapy of small cell lung cancer. Ó 2010 Elsevier Ltd. All rights reserved. 1. Introduction Lung cancer is the number one cause of cancer-related death worldwide, with more than 1 million deaths per year. Despite improvements in radiotherapy and chemotherapy, the five years survival rate remains below 15%. Incidence of small cell lung carcinoma (SCLC) has declined below 15% compared with 20–25% previously. 1–3 However, the outcome of extensive stage 0959-8049/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.ejca.2010.03.021 * Corresponding author: Address: Molecular and Cellular Biology lab of Gemboux Agro-Bio Tech, 13, avenue Mare ´ chal Juin, 5030 Gembloux, Belgium. Tel.: +32 81622157; fax: +32 81613888. E-mail address: Luc.Willems@ulg.ac.be (L. Willems). e Equally contributing authors. EUROPEAN JOURNAL OF CANCER 46 (2010) 1724 – 1734 available at www.sciencedirect.com journal homepage: www.ejconline.com