Department of Internal Medicine, Yonsei University College of Medicine, 250 Seongsanno, Seodaemun-gu, Seoul 120-752, Korea.
J Pharmacol Exp Ther. 2010 Nov;335(2):389-400. doi: 10.1124/jpet.110.169367. Epub 2010 Aug 10.
Given that parthenolide (PTL) is an effective antileukemic agent, identifying molecular markers that predict response to PTL is important. We evaluated the role of myeloperoxidase (MPO) in determining the sensitivity of leukemia cells to PTL-induced apoptosis. In this study, the level of PTL-induced generation of reactive oxygen species (ROS) and apoptosis was significantly higher in the MPO-high leukemia cell lines compared with the MPO-low leukemia cell lines. Pretreatment of MPO-high leukemia cells with a MPO-specific inhibitor, 4-aminobenzoic acid hydrazide, or a MPO-specific small interfering RNA (siRNA) abrogated the PTL-induced ROS generation and apoptosis, indicating that MPO plays a crucial role in PTL-induced apoptosis in leukemia cells. PTL-induced apoptosis was accompanied by down-regulation of nuclear factor-κB, Bcl-xL, Mcl-1, X-linked inhibitor of apoptosis protein, and survivin and selectively observed in primary acute myeloid leukemia (AML) cells expressing higher levels of MPO (≥50%) while sparing both AML cells with lower MPO and normal CD34-positive (CD34+) normal bone marrow cells. The extent of PTL-induced apoptosis of the CD34+CD38- cell fraction was significantly greater in the MPO-high AML cases, compared with the MPO-low AML (P < 0.01) and normal CD34+ marrow cells (P < 0.01). Nonobese diabetic/severe combined immunodeficient human leukemia mouse model also revealed that PTL preferentially targets the MPO-high AML cells. Our data suggest that MPO plays a crucial role in determining the susceptibility of leukemia cells to PTL-induced apoptosis. PTL can be considered a promising leukemic stem cell-targeted therapy for AML expressing high levels of MPO.
鉴于小白菊内酯（PTL）是一种有效的抗白血病药物，因此确定预测其对 PTL 反应的分子标志物非常重要。我们评估了髓过氧化物酶（MPO）在确定白血病细胞对 PTL 诱导凋亡的敏感性中的作用。在这项研究中，与 MPO 低的白血病细胞系相比，MPO 高的白血病细胞系中 PTL 诱导的活性氧（ROS）产生和凋亡的水平明显更高。用 MPO 特异性抑制剂 4-氨基苯甲酰胺肼或 MPO 特异性小干扰 RNA（siRNA）预处理 MPO 高的白血病细胞可消除 PTL 诱导的 ROS 生成和凋亡，表明 MPO 在白血病细胞中对 PTL 诱导的凋亡起关键作用。PTL 诱导的凋亡伴随着核因子-κB、Bcl-xL、Mcl-1、X 连锁凋亡抑制蛋白和生存素的下调，并且仅在表达更高水平 MPO（≥50%）的原发性急性髓系白血病（AML）细胞中观察到，同时对 MPO 水平较低的 AML 细胞和正常 CD34+（CD34+）正常骨髓细胞均无影响。与 MPO 低的 AML（P < 0.01）和正常 CD34+骨髓细胞（P < 0.01）相比，MPO 高的 AML 病例中 CD34+CD38-细胞部分的 PTL 诱导凋亡程度明显更大。非肥胖型糖尿病/严重联合免疫缺陷人白血病小鼠模型也表明 PTL 优先靶向 MPO 高的 AML 细胞。我们的数据表明，MPO 在决定白血病细胞对 PTL 诱导的凋亡的敏感性中起关键作用。PTL 可被视为针对表达高水平 MPO 的 AML 的有前途的白血病干细胞靶向治疗方法。
