Valproic Acid, a Histone Deacetylase Inhibitor, Induces Apoptosis, Inhibits Proliferation, and Synergizes With Chemotherapy: The Rationale to Combine it for the Treatment of B-Cell Chronic Lymphocytic Leukemia

Abstract

Brief Abstract In this work, we showed that valproic acid (VPA) induces apoptosis by downregulating several anti-apoptotic genes and by upregulating pro-apoptotic genes. VPA also inhibits proliferation by disturbing many cell cycle messenger RNAs and potentiates cytotoxic effects of chemotherapeutic agents, suggesting its introduction in B-CLL treatment. Full Abstract Background Epigenetic code modifications by histone deacetylase (HDAC) inhibitors have recently been proposed as potential new therapies for hematologic malignancies. B-cell chronic lymphocytic leukemia (B-CLL) remains incurable despite the introduction of new treatments. B-CLL cells are characterized by an apoptosis defect rather than an excessive proliferation, but proliferation areas can be found in some organs such as bone marrow and lymph nodes. Patients and Methods In this study, we analyzed the gene expression modifications in B-CLL cells after treatment with valproic acid (VPA), a well-tolerated anti-epileptic drug with HDAC inhibitory activity. B-CLL cells obtained from 14 patients were exposed in vitro to a concentration of 1 mM VPA during 4 h. VPA effects on gene expression were studied before and after exposure using Affymetrix technology, and some identified genes were validated by real-time polymerase chain reaction and Western blot. Results We observed that VPA induced apoptosis by downregulating several anti-apoptotic genes and by upregulating pro-apoptotic genes. VPA inhibited the proliferation of CpG/IL2-stimulated B-CLL cells and modulated many cell cycle messenger RNAs. Furthermore, VPA significantly increased chemosensitivity to fludarabine, flavopiridol, bortezomib, thalidomide, and lenalidomide. Conclusion (1) Exposure of B-CLL cells to VPA induces apoptosis, inhibits proliferation, and potentiates cytotoxic effects of chemotherapeutic agents. (2) These data strongly suggest that VPA combined with cytotoxic chemotherapy is particularly appealing in B-CLL treatment. Based on our data and literature data (Bokelmann et al; Bouzar et al), we have planed to study, in a multicentric phase I/II Belgian clinical trial, the combination of VPA and 2CDA (cladribine).