Bokelmann Imke, Mahlknecht Ulrich
Department of Hematology/Oncology, University of Heidelberg Medical Center, Im Neuenheimer Feld 410, Heidelberg, Germany.
Mol Med. 2008 Jan-Feb;14(1-2):20-7. doi: 10.2119/2007-00084.Bokelmann.
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.
慢性淋巴细胞白血病（CLL）是发达国家成年人中最常见的白血病之一。尽管癌症治疗取得了重大进展，但CLL仍然无法治愈。该疾病的主要特征是由于异常凋亡导致循环B细胞存活时间延长。在本研究中，我们观察到丙戊酸（VPA），一种成熟的组蛋白脱乙酰酶（HDAC）抑制剂，通过半胱天冬酶激活，经外在和内在凋亡途径介导CLL细胞的体外凋亡，这由半胱天冬酶蛋白8和9的激活以及促凋亡蛋白BID的裂解所表明。由于VPA治疗导致bcl-2 mRNA水平降低，Bcl-2/Bax比值下降。根据本研究呈现的结果，我们已确定HDAC抑制剂VPA可恢复CLL细胞中的凋亡途径，从而恢复其凋亡能力。
