On-Target Effect of FK866, a Nicotinamide Phosphoribosyl Transferase Inhibitor, by Apoptosis-Mediated Death in Chronic Lymphocytic Leukemia Cells
On-Target Effect of FK866, a Nicotinamide Phosphoribosyl Transferase Inhibitor, by Apoptosis-Mediated Death in Chronic Lymphocytic Leukemia Cells
复制标题
DOI：
10.1158/1078-0432.ccr-14-0624
复制
发表时间：
2014-09-15
影响因子：
11.5
通讯作者：
Banerji, Versha
中科院分区：
文献类型：
--
作者：
Gehrke, Iris;Bouchard, Eric D. J.;Banerji, Versha
目的：慢性淋巴细胞白血病（CLL）尽管治疗方法不断进步，但仍无法治愈.在这项研究中，我们的特点烟酰胺磷酸核糖转移酶（NAMPT）抑制FK 866在原代CLL细胞的患者与各种临床预后markets.Experimental设计：CLL细胞用FK 866处理，通过膜联蛋白V/PI染色评估活力的影响。FK 866的功能分析包括细胞NAD、ATP、线粒体膜电位（MMP）、活性氧（ROS）和凋亡信号的时间和浓度依赖性评价。还评估了FK 866对氟达拉滨的化学增敏潜力。预后标志物与药物responsibility.Results相关：FK 866诱导CLL细胞死亡的细胞NAD含量耗尽的第1天，其次是在ATP下降的第2天。在第3天，我们观察到MMP的损失、ROS的增加和凋亡信号的诱导。通过NAD介导的NAD和ATP损失的拯救、凋亡信号传导和活力证实了FK 866的靶向活性。对FK 866的反应与大多数预后标志物无关。淋巴细胞倍增时间短和CD 38阳性状态需要更高的剂量，而体外对氟达拉滨耐药的CLL细胞和来自del17p13.1患者的CLL细胞对FK 866同样敏感。FK 866不上调p53靶点p21，p53激活剂Nutlin也不改善FK 866介导的细胞死亡。此外，氟达拉滨和FK 866在临床相关concentration.Conclusions：NAMPT抑制FK 866可能是一种潜在的治疗CLL，包括del17p13.1或其他高危功能的患者。FK 866可补充标准药物，以增强其疗效和/或允许减少剂量以改善耐受性。(C)2014年AACR。
Purpose: Chronic lymphocytic leukemia (CLL) remains incurable despite advances in therapy. In this study, we characterize the effect of nicotinamide phosphoribosyltransferase (NAMPT) inhibition by FK866 in primary CLL cells from patients with various clinical prognostic markers.Experimental Design: CLL cells were treated with FK866 to assess viability by Annexin V/PI staining. Functional analysis of FK866 included time-and concentration-dependent evaluation of cellular NAD, ATP, mitochondrial membrane potential (MMP), reactive oxygen species (ROS), and apoptotic signaling. Chemosensitization potential by FK866 to fludarabine was also assessed. Prognostic markers were correlated with drug response.Results: FK866 induced CLL cell death by depleting cellular NAD content by day 1, followed by a drop in ATP on day 2. We observed loss of MMP, ROS increase, and induction of apoptotic signaling at day 3. On-target activity of FK866 was confirmed by NAD-mediated rescue of NAD and ATP loss, apoptotic signaling, and viability. The response to FK866 was independent of most prognostic markers. Higher doses were required with short lymphocyte doubling time and positive CD38 status, whereas CLL cells resistant to fludarabine in vitro and from patients with del17p13.1 were equally sensitive to FK866. FK866 did not upregulate the p53-target p21, nor did the p53 activator Nutlin improve FK866-mediated cell death. Furthermore, fludarabine and FK866 were synergistic at clinically relevant concentrations.Conclusions: NAMPT inhibition by FK866 may be a potential treatment for CLL, including patients with del17p13.1 or other high-risk features. FK866 may complement standard agents to enhance their efficacy and/or allow dose reduction for improved tolerability. (C) 2014 AACR.