Oncology Division, University of Navarra, Pamplona, Spain.
Leukemia. 2012 Jul;26(7):1517-26. doi: 10.1038/leu.2012.31. Epub 2012 Feb 6.
Histone deacetylases (HDACs) have been identified as therapeutic targets due to their regulatory function in chromatin structure and organization. Here, we analyzed the therapeutic effect of LBH589, a class I-II HDAC inhibitor, in acute lymphoblastic leukemia (ALL). In vitro, LBH589 induced dose-dependent antiproliferative and apoptotic effects, which were associated with increased H3 and H4 histone acetylation. Intravenous administration of LBH589 in immunodeficient BALB/c-RAG2(-/-)γc(-/-) mice in which human-derived T and B-ALL cell lines were injected induced a significant reduction in tumor growth. Using primary ALL cells, a xenograft model of human leukemia in BALB/c-RAG2(-/-)γc(-/-) mice was established, allowing continuous passages of transplanted cells to several mouse generations. Treatment of mice engrafted with T or B-ALL cells with LBH589 induced an in vivo increase in the acetylation of H3 and H4, which was accompanied with prolonged survival of LBH589-treated mice in comparison with those receiving vincristine and dexamethasone. Notably, the therapeutic efficacy of LBH589 was significantly enhanced in combination with vincristine and dexamethasone. Our results show the therapeutic activity of LBH589 in combination with standard chemotherapy in pre-clinical models of ALL and suggest that this combination may be of clinical value in the treatment of patients with ALL.
组蛋白去乙酰化酶 (HDACs) 因其在染色质结构和组织中的调节功能而被确定为治疗靶点。在这里，我们分析了 LBH589（一种 I-II 类 HDAC 抑制剂）在急性淋巴细胞白血病（ALL）中的治疗效果。在体外，LBH589 诱导了剂量依赖性的抗增殖和凋亡作用，这与增加 H3 和 H4 组蛋白乙酰化有关。在注入人源性 T 和 B-ALL 细胞系的免疫缺陷 BALB/c-RAG2(-/-)γc(-/-)小鼠中静脉给予 LBH589 可显著抑制肿瘤生长。使用原发性 ALL 细胞，在 BALB/c-RAG2(-/-)γc(-/-)小鼠中建立了人类白血病的异种移植模型，允许移植细胞连续传代到几个小鼠代。用 LBH589 治疗移植了 T 或 B-ALL 细胞的小鼠，可在体内增加 H3 和 H4 的乙酰化，与接受长春新碱和地塞米松治疗的小鼠相比，LBH589 治疗的小鼠的存活时间延长。值得注意的是，LBH589 与长春新碱和地塞米松联合使用的治疗效果显著增强。我们的研究结果显示了 LBH589 与标准化疗联合应用于 ALL 临床前模型中的治疗活性，并表明这种联合应用可能在 ALL 患者的治疗中具有临床价值。
