Division of Stem Cell Regulation, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan.
Leukemia. 2010 Oct;24(10):1760-8. doi: 10.1038/leu.2010.157. Epub 2010 Aug 5.
Anti-CD20 antibody rituximab is now essential for the treatment of CD20-positive B-cell lymphomas. Decreased expression of CD20 is one of the major mechanisms underlying both innate and acquired resistance to rituximab. In this study, we show that histone deacetylase (HDAC) inhibitors augment the cytotoxic activity of rituximab by enhancing the surface expression of CD20 antigen on lymphoma cells. HDAC inhibitors, valproic acid (VPA) and romidepsin, increased CD20 expression at protein and mRNA levels in B-cell lymphoma cell lines with relatively low CD20 expression levels. The VPA-mediated increase in CD20 expression occurred at 1 m, which is clinically achievable and safe, but insufficient for inducing cell death. Chromatin immunoprecipitation assays revealed that HDAC inhibitors transactivated the CD20 gene through promoter hyperacetylation and Sp1 recruitment. HDAC inhibitors potentiated the activity of rituximab in complement-dependent cytotoxic assays. In mouse lymphoma models, HDAC inhibitors enhanced CD20 expression along with histone hyperacetylation in transplanted cells, and acted synergistically with rituximab to retard their growth. The combination with HDAC inhibitors may serve as an effective strategy to overcome rituximab resistance in B-cell lymphomas.
抗 CD20 抗体利妥昔单抗现在是治疗 CD20 阳性 B 细胞淋巴瘤的必备药物。CD20 表达降低是导致利妥昔单抗先天和获得性耐药的主要机制之一。在这项研究中，我们表明组蛋白去乙酰化酶 (HDAC) 抑制剂通过增强淋巴瘤细胞表面 CD20 抗原的表达来增强利妥昔单抗的细胞毒性活性。HDAC 抑制剂丙戊酸 (VPA) 和罗米地辛在 CD20 表达水平相对较低的 B 细胞淋巴瘤细胞系中，在蛋白和 mRNA 水平上增加了 CD20 的表达。VPA 介导的 CD20 表达增加发生在 1μM，这在临床上是可行且安全的，但不足以诱导细胞死亡。染色质免疫沉淀分析表明，HDAC 抑制剂通过启动子超乙酰化和 Sp1 募集来激活 CD20 基因。HDAC 抑制剂增强了补体依赖性细胞毒性测定中利妥昔单抗的活性。在小鼠淋巴瘤模型中，HDAC 抑制剂增强了移植细胞中的 CD20 表达和组蛋白的超乙酰化作用，并与利妥昔单抗协同作用，延缓了它们的生长。与 HDAC 抑制剂联合使用可能是克服 B 细胞淋巴瘤中利妥昔单抗耐药的有效策略。
