In vivo anti-myeloma activity and modulation of gene expression profile induced by valproic acid, a histone deacetylase inhibitor.
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.
Neri
Paola
P
Medical Oncology Unit, Magna Graecia University and Tommaso Campanella Cancer Center, Campus Salvatore Venuta, Catanzaro, Italy.
Tagliaferri
Pierosandro
P
Di Martino
Maria Teresa
MT
Calimeri
Teresa
T
Amodio
Nicola
N
Bulotta
Alessandra
A
Ventura
Monica
M
Eramo
Pasqua Orietta
PO
Viscomi
Caterina
C
Arbitrio
Mariamena
M
Rossi
Marco
M
Caraglia
Michele
M
Munshi
Nikhil C
NC
Anderson
Kenneth C
KC
Tassone
Pierfrancesco
P
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D009368:Neoplasm Transplantation; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D014635:Valproic Acid / Q000494:pharmacology / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D014635:Valproic Acid