Department of Chemistry and Biochemistry, University of California, Los Angeles, CA, USA.
Leuk Lymphoma. 2011 Aug;52(8):1544-55. doi: 10.3109/10428194.2011.570821. Epub 2011 Jun 23.
Over the past decade, histone deacetylase inhibitors have increasingly been used to treat various malignancies. Tubacin (tubulin acetylation inducer) is a small molecule that inhibits histone deacetylase 6 (HDAC6) and induces acetylation of α-tubulin. We observed a higher antiproliferative effect of tubacin in acute lymphoblastic leukemia (ALL) cells than in normal hematopoietic cells. Treatment with tubacin led to the induction of apoptotic pathways in both pre-B and T cell ALL cells at a 50% inhibitory concentration (IC(50)) of low micromolar concentrations. Acetylation of α-tubulin increases within the first 30 min following treatment of ALL cells with tubacin. We also observed an accumulation of polyubiquitinated proteins and poly(ADP-ribose) polymerase (PARP) cleavage. Furthermore, the signaling pathways activated by tubacin appear to be distinct from those observed in multiple myeloma. In this article, we demonstrate that tubacin enhances the effects of chemotherapy to treat primary ALL cells in vitro and in vivo. These results suggest that targeting HDAC6 alone or in combination with chemotherapy could provide a novel approach to treat ALL.
在过去的十年中，组蛋白去乙酰化酶抑制剂已越来越多地被用于治疗各种恶性肿瘤。Tubacin（微管乙酰化诱导剂）是一种小分子，可抑制组蛋白去乙酰化酶 6（HDAC6）并诱导α-微管蛋白乙酰化。我们观察到 Tubacin 在急性淋巴细胞白血病（ALL）细胞中的抗增殖作用高于正常造血细胞。在低微摩尔浓度的 50%抑制浓度（IC50）下，Tubacin 处理可诱导前 B 和 T 细胞 ALL 细胞中凋亡途径的诱导。在用 Tubacin 处理 ALL 细胞后的最初 30 分钟内，α-微管蛋白的乙酰化增加。我们还观察到多聚泛素化蛋白和聚（ADP-核糖）聚合酶（PARP）裂解的积累。此外，Tubacin 激活的信号通路似乎与多发性骨髓瘤中观察到的信号通路不同。在本文中，我们证明 Tubacin 增强了体外和体内化疗治疗原发性 ALL 细胞的效果。这些结果表明，单独靶向 HDAC6 或与化疗联合使用可能为治疗 ALL 提供一种新方法。
