文章：

丙戊酸和氟达拉滨在慢性淋巴细胞白血病（CLL）细胞中的协同凋亡反应涉及溶酶体蛋白酶组织蛋白酶B

Synergistic apoptotic response between valproic acid and fludarabine in chronic lymphocytic leukaemia (CLL) cells involves the lysosomal protease cathepsin B

原文发布日期：2013-10-18

DOI: 10.1038/bcj.2013.50

类型: Original Article

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英文摘要：

Fludarabine, a nucleoside analogue, is commonly used in combination with other agents for the treatment of chronic lymphocytic leukaemia (CLL). In previous studies, valproic acid (VPA), an inhibitor of histone deacetylases, combined with fludarabine to synergistically increase apoptotic cell death in CLL cells. In the present study, we found that the combination of fludarabine and VPA decreases the level of the anti-apoptotic proteins Mcl-1 and XIAP in primary CLL cells. Treatment with fludarabine alone, or in combination with VPA, led to the loss of lysosome integrity, and chemical inhibition of the lysosomal protease cathepsin B, using CA074-Me, was sufficient to reduce apoptosis. VPA treatment increased cathepsin B levels and activities in primary CLL cells, thereby priming CLL cells for lysosome-mediated cell death. Six previously treated patients with relapsed CLL were treated with VPA, followed by VPA/fludarabine combination. The combined therapy resulted in reduced lymphocyte count in five out of six and reduced lymph node sizes in four out of six patients. In vivo VPA treatment increased histone-3 acetylation and cathepsin B expression levels. Thus, the synergistic apoptotic response with VPA and fludarabine in CLL is mediated by cathepsin B activation leading to a decrease in the anti-apoptotic proteins.

摘要翻译： 

氟达拉滨是一种核苷类似物，常与其他药物联合用于治疗慢性淋巴细胞白血病（CLL）。既往研究表明，组蛋白去乙酰化酶抑制剂丙戊酸（VPA）与氟达拉滨联用可协同促进CLL细胞的凋亡。本研究发现，氟达拉滨与VPA联用可降低原发性CLL细胞中抗凋亡蛋白Mcl-1和XIAP的水平。单独使用氟达拉滨或与VPA联用均会导致溶酶体完整性丧失，而使用CA074-Me化学抑制溶酶体蛋白酶组织蛋白酶B足以减少细胞凋亡。VPA处理能提高原发性CLL细胞中组织蛋白酶B的含量和活性，从而促使CLL细胞发生溶酶体介导的细胞死亡。对六例既往接受过治疗的复发CLL患者先给予VPA治疗，后续采用VPA/氟达拉滨联合方案治疗。联合治疗使六分之五的患者淋巴细胞计数降低，六分之四的患者淋巴结体积缩小。体内VPA治疗可增强组蛋白-3乙酰化并提高组织蛋白酶B表达水平。因此，VPA与氟达拉滨在CLL中产生的协同凋亡效应是通过激活组织蛋白酶B、降低抗凋亡蛋白水平实现的。

原文链接：

Synergistic apoptotic response between valproic acid and fludarabine in chronic lymphocytic leukaemia (CLL) cells involves the lysosomal protease cathepsin B