In vivo anti-myeloma activity and modulation of gene expression profile induced by valproic acid, a histone deacetylase inhibitor

Paola Neri, Pierosandro Tagliaferri, Maria Teresa Di Martino, Teresa Calimeri, Nicola Amodio, Alessandra Bulotta, Monica Ventura, Pasqua Orietta Eramo, Caterina Viscomi, Mariamena Arbitrio, Marco Rossi, Michele Caraglia, Nikhil C. Munshi, Kenneth C. Anderson, Pierfrancesco Tassone

Research output: Contribution to journalArticle

Abstract

Valproic acid (VPA) is a well-tolerated anticonvulsant that exerts anti-tumour activity as a histone deacetylase inhibitor. This study investigated the in vitro and in vivo activity of VPA against multiple myeloma (MM) cells. In vitro exposure of interleukin-6-dependent or -independent MM cells to VPA inhibited cell proliferation in a time- and dose-dependent manner and induced apoptosis. In a cohort of severe combined immunodeficiency mice bearing human MM xenografts, VPA induced tumour growth inhibition and survival advantage in treated animals versus controls. Flow cytometric analysis performed on MM cells from excised tumours showed increase of G0-G1 and a decreased G2/M- and S-phase following VPA treatment, indicating in vivo effects of VPA on cell cycle regulation. Gene expression profiling of MM cells exposed to VPA showed downregulation of genes involved in cell cycle progression, DNA replication and transcription, as well as upregulation of genes implicated in apoptosis and chemokine pathways. Pathfinder analysis of gene array data identified cell growth, cell cycle, cell death, as well as DNA replication and repair as the most important signalling networks modulated by VPA. Taken together, our data provide the preclinical rationale for VPA clinical evaluation as a single agent or in combination, to improve patient outcome in MM.

Original languageEnglish
Pages (from-to)520-531
Number of pages12
JournalBritish Journal of Haematology
Volume143
Issue number4
DOIs
Publication statusPublished - Nov 2008

Keywords

  • Histone deacetylase inhibitor
  • Multiple myeloma
  • Pathfinder analysis
  • SCID mice
  • Valproic acid

ASJC Scopus subject areas

  • Hematology

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    Neri, P., Tagliaferri, P., Di Martino, M. T., Calimeri, T., Amodio, N., Bulotta, A., Ventura, M., Eramo, P. O., Viscomi, C., Arbitrio, M., Rossi, M., Caraglia, M., Munshi, N. C., Anderson, K. C., & Tassone, P. (2008). In vivo anti-myeloma activity and modulation of gene expression profile induced by valproic acid, a histone deacetylase inhibitor. British Journal of Haematology, 143(4), 520-531. https://doi.org/10.1111/j.1365-2141.2008.07387.x