Valproate, a Histone Deacetylase Inhibitor, Enhances Purine Nucleoside Analogues Induced Apoptosis of B-Chronic Lymphocytic Leukemia Cells.

Resistance to chemotherapy and drug toxicity are two major concerns of Chronic Lymphocytic Leukemia (B-CLL) treatment by Purine Nucleoside Analogs (PNA, i.e. fludarabine and cladribine). We hypothesized that targeting epigenetic changes might address these issues and evaluated the effect of the histone deacetylase (HDAC) inhibitor valproate (VPA) at a clinically relevant concentration. We show that VPA acts in a highly synergistic/additive manner with 9-ß-D-arabinosyl-2-fluoroadenine-5′-monophosphate (F-ara-AMP, fludarabine, 1μM) and 2-chloro-2′-deoxyadenosine (CdA, cladribine, 1μM) to induce apoptosis of CLL cells. VPA, but neither fludarabine nor cladribine, enhances the production of Reactive Oxygen Species (ROS) and inhibition of ROS with N-acetylcysteine decreases apoptosis of CLL cells. VPA-induced apoptosis is caspase-dependent and involves the extrinsic initiation pathway. VPA stimulates hyperphosphorylation of p42/p44 Erk as well as overexpression of Bax, cytochrome c and Fas. These observations support a potential use of VPA alone or in combination with nucleosidic analogs in CLL therapeutic protocols allowing a reduction of their effective doses or improving their efficacy in PNA-resistant patients.