Antileukemic activity of valproic acid in chronic lymphocytic leukemia B cells defined by microarray analysis.
Epigenetic code modifications by histone deacetylase inhibitors have recently been proposed as potential new therapies for hematological malignancies. Chronic lymphocytic leukemia (CLL) remains incurable despite the introduction of new treatments. CLL B cells are characterized by an apoptosis defect rather than excessive proliferation, but proliferation centers have been found in organs such as the bone marrow and lymph nodes. In this study, we analyzed gene expression modifications in CLL B cells after treatment with valproic acid (VPA), a well-tolerated anti-epileptic drug with HDAC inhibitory activity. CLL B cells obtained from 14 patients were treated in vitro with a concentration of 1 mM VPA for 4 h. VPA effects on gene expression were thereafter studied using Affymetrix technology, and some identified genes were validated by real-time PCR and western blot. We observed that VPA induced apoptosis by downregulating several anti-apoptotic genes and by upregulating pro-apoptotic genes. Furthermore, VPA significantly increased chemosensitivity to fludarabine, flavopiridol, bortezomib, thalidomide and lenalidomide. VPA inhibited the proliferation of CpG/IL2-stimulated CLL B cells and modulated many cell cycle messenger RNAs. In conclusion, exposure of CLL B cells to VPA induced apoptosis, potentiated chemotherapeutic agent effects and inhibited proliferation. These data strongly suggest the use of VPA in CLL treatment, particularly in combination with antileukemia agents.
Stamatopoulos
B
B
Laboratory of Experimental Hematology, Faculty of Medicine, Institut Jules Bordet, Université Libre de Bruxelles, Boulevard de Waterloo 121, Brussels, Belgium. bstamato@ulb.ac.be
Meuleman
N
N
De Bruyn
C
C
Mineur
P
P
Martiat
P
P
Bron
D
D
Lagneaux
L
L
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D020869:Gene Expression Profiling / Q000379:methods*; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D014635:Valproic Acid / Q000494:pharmacology*
D051017:Apoptosis Regulatory Proteins; D056572:Histone Deacetylase Inhibitors; D014635:Valproic Acid