Division of Hematology/Oncology, Department of Biochemistry, and Massey Cancer Center, Virginia Commonwealth University Health Sciences Center, Richmond, Virginia 23298, USA.
Clin Cancer Res. 2011 May 15;17(10):3219-32. doi: 10.1158/1078-0432.CCR-11-0234. Epub 2011 Apr 7.
The purpose of this study was to determine whether histone deacetylase (HDAC) inhibitors (HDACI) such as vorinostat or entinostat (SNDX-275) could increase the lethality of the dual Bcr/Abl-Aurora kinase inhibitor KW-2449 in various Bcr/Abl(+) human leukemia cells, including those resistant to imatinib mesylate (IM).
Bcr/Abl(+) chronic myelogenous leukemia (CML) and acute lymphoblastic leukemia (ALL) cells, including those resistant to IM (T315I, E255K), were exposed to KW-2449 in the presence or absence of vorinostat or SNDX-275, after which apoptosis and effects on signaling pathways were examined. In vivo studies combining HDACIs and KW2449 were carried out by using a systemic IM-resistant ALL xenograft model.
Coadministration of HDACIs synergistically increased KW-2449 lethality in vitro in multiple CML and Ph(+) ALL cell types including human IM resistant cells (e.g., BV-173/E255K and Adult/T315I). Combined treatment resulted in inactivation of Bcr/Abl and downstream targets (e.g., STAT5 and CRKL), as well as increased reactive oxygen species (ROS) generation and DNA damage (γH2A.X). The latter events and cell death were significantly attenuated by free radical scavengers (TBAP). Increased lethality was also observed in primary CD34(+) cells from patients with CML, but not in normal CD34(+) cells. Finally, minimally active vorinostat or SNDX275 doses markedly increased KW2449 antitumor effects and significantly prolonged the survival of murine xenografts bearing IM-resistant ALL cells (BV173/E255K).
HDACIs increase KW-2449 lethality in Bcr/Abl(+) cells in association with inhibition of Bcr/Abl, generation of ROS, and induction of DNA damage. This strategy preferentially targets primary Bcr/Abl(+) hematopoietic cells and exhibits enhanced in vivo activity. Combining KW-2449 with HDACIs warrants attention in IM-resistant Bcr/Abl(+) leukemias.
本研究旨在确定组蛋白去乙酰化酶（HDAC）抑制剂（如伏立诺他或恩替诺特）是否可以增加双重 Bcr/Abl-Aurora 激酶抑制剂 KW-2449 在各种 Bcr/Abl(+)人白血病细胞中的致死率，包括对甲磺酸伊马替尼（IM）耐药的细胞。
Bcr/Abl(+)慢性髓性白血病（CML）和急性淋巴细胞白血病（ALL）细胞，包括对 IM（T315I、E255K）耐药的细胞，在暴露于 KW-2449 时或不暴露于 KW-2449 时，加入伏立诺他或 SNDX-275，然后检查细胞凋亡和信号通路的影响。通过使用全身性 IM 耐药 ALL 异种移植模型进行了将 HDACIs 与 KW2449 联合使用的体内研究。
在包括对 IM 耐药的人类细胞（例如 BV-173/E255K 和 Adult/T315I）在内的多种 CML 和 Ph(+)ALL 细胞类型中，联合使用 HDACIs 可协同增加 KW-2449 的体外致死率。联合治疗导致 Bcr/Abl 及其下游靶标（如 STAT5 和 CRKL）失活，以及活性氧（ROS）生成和 DNA 损伤（γH2A.X）增加。这些事件和细胞死亡可被自由基清除剂（TBAP）显著抑制。在来自 CML 患者的原代 CD34(+)细胞中也观察到了增加的致死率，但在正常 CD34(+)细胞中没有观察到。最后，低活性伏立诺他或 SNDX275 剂量显著增加 KW2449 的抗肿瘤作用，并显著延长了携带 IM 耐药 ALL 细胞（BV173/E255K）的小鼠异种移植物的存活时间。
HDACIs 与抑制 Bcr/Abl、生成 ROS 和诱导 DNA 损伤一起，增加了 Bcr/Abl(+)细胞中 KW-2449 的致死率。该策略优先靶向原代 Bcr/Abl(+)造血细胞，并在体内显示出增强的活性。将 KW-2449 与 HDACIs 联合使用值得在 IM 耐药的 Bcr/Abl(+)白血病中关注。
