TY - JOUR
T1 - In vivo anti-myeloma activity and modulation of gene expression profile induced by valproic acid, a histone deacetylase inhibitor
AU - Neri, Paola
AU - Tagliaferri, Pierosandro
AU - Di Martino, Maria Teresa
AU - Calimeri, Teresa
AU - Amodio, Nicola
AU - Bulotta, Alessandra
AU - Ventura, Monica
AU - Eramo, Pasqua Orietta
AU - Viscomi, Caterina
AU - Arbitrio, Mariamena
AU - Rossi, Marco
AU - Caraglia, Michele
AU - Munshi, Nikhil C.
AU - Anderson, Kenneth C.
AU - Tassone, Pierfrancesco
PY - 2008/11
Y1 - 2008/11
N2 - 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.
AB - 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.
KW - Histone deacetylase inhibitor
KW - Multiple myeloma
KW - Pathfinder analysis
KW - SCID mice
KW - Valproic acid
UR - http://www.scopus.com/inward/record.url?scp=54849407184&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=54849407184&partnerID=8YFLogxK
U2 - 10.1111/j.1365-2141.2008.07387.x
DO - 10.1111/j.1365-2141.2008.07387.x
M3 - Article
C2 - 18986388
AN - SCOPUS:54849407184
VL - 143
SP - 520
EP - 531
JO - British Journal of Haematology
JF - British Journal of Haematology
SN - 0007-1048
IS - 4
ER -