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In vivo anti‐myeloma activity and modulation of gene expression profile induced by valproic acid, a histone deacetylase inhibitor
Author(s) -
Neri Paola,
Tagliaferri Pierosandro,
Di Martino Maria Teresa,
Calimeri Teresa,
Amodio Nicola,
Bulotta Alessandra,
Ventura Monica,
Eramo Pasqua Orietta,
Viscomi Caterina,
Arbitrio Mariamena,
Rossi Marco,
Caraglia Michele,
Munshi Nikhil C.,
Anderson Kenneth C.,
Tassone Pierfrancesco
Publication year - 2008
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/j.1365-2141.2008.07387.x
Subject(s) - cancer research , cell cycle , downregulation and upregulation , histone deacetylase inhibitor , histone deacetylase , in vivo , cell growth , biology , apoptosis , cell cycle checkpoint , histone , gene , biochemistry , microbiology and biotechnology
Summary 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 G 0 –G 1 and a decreased G 2 /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.