Valproic Acid Sensitizes Chronic Lymphocytic Leukemia Cells to Apoptosis and Restores the Balance Between Pro- and Antiapoptotic Proteins
Chronic lymphocytic leukemia (CLL) is one of the most common leukemias in adults in the developed world. Despite significant advances in the treatment of cancer, CLL remains incurable. The main feature of the disease is the generation of circulating B-cells with prolonged survival caused by aberrant apoptosis. In this study, we observe that valproic acid (VPA), a well-established histone deacetylase (HDAC) inhibitor, mediates apoptosis in CLL cells ex vivo through caspase activation via both the extrinsic and the intrinsic apoptosis pathways, as indicated by the activation of the caspase proteins 8 and 9, and cleavage of the proapoptotic protein BID. The Bcl-2/Bax ratio was decreased as a consequence of decreased bcl-2 mRNA levels in response to treatment with VPA. With the results presented in this study, we have identified the HDAC inhibitor VPA as restoring the apoptotic pathways in CLL cells and thus their ability to undergo apoptosis.
This work was supported by grants from the Deutsche José Carreras Leukämie-Stiftung e.V. (DJCLS R 05/11), the Deutsche Forschungsgemeinschaft (MA 2057/2-4), and the German Cancer Research Center (DKFZ) intramural funding program. We thank Manfred Hensel for patient samples and Volker Eckstein for help with flow cytometry. This work has in part been carried out at the University of Heidelberg Medical Center and the German Cancer Research Center (DKFZ).
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