The sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cells
The sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cells
复制标题
DOI：
10.1182/blood-2004-10-4135
复制
发表时间：
2005-06-01
期刊：
影响因子：
20.3
通讯作者：
Jordan, CT
中科院分区：
文献类型：
--
作者：
Guzman, ML;Rossi, RM;Jordan, CT
近期研究已将恶性干细胞描述为急性和慢性髓性白血病（AML和CML）的起始、生长以及潜在复发的核心因素。由于它们在发病机制中具有重要作用，罕见且生物学特性独特的白血病干细胞（LSCs）成为治疗干预的关键靶点。然而，到目前为止，很少有药物被证明可直接针对LSC群体。目前的研究表明，小白菊内酯（PTL），一种天然小分子，可诱导原发性人类AML细胞和急变期CML（bcCML）细胞发生强烈的凋亡，同时不损害正常造血细胞。此外，利用体外集落形成试验对祖细胞以及利用非肥胖糖尿病/重度联合免疫缺陷（NOD/SCID）异种移植模型对干细胞进行分析表明，PTL还优先针对AML祖细胞和干细胞群体。值得注意的是，与标准化疗药物阿糖胞苷（Ara - C）相比，PTL对白血病细胞具有更强的特异性。PTL介导的凋亡分子机制与核因子κB（NF - κB）的抑制、p53的促凋亡激活以及活性氧（ROS）增加密切相关。基于这些发现，我们提出PTL的活性可触发LSC特异性凋亡，因此它代表了一类对LSC靶向治疗可能具有重要意义的新型药物。
Recent studies have described malignant stem cells as central to the initiation, growth, and potential relapse of acute and chronic myelogenous leukemia (AML and CML). Because of their important role in pathogenesis, rare and biologically distinct leukemia stem cells (LSCs) represent a critical target for therapeutic intervention. However, to date, very few agents have been shown to directly target the LSC population. The present studies demonstrate that parthenolide (PTL), a naturally occurring small molecule, induces robust apoptosis in primary human AML cells and blast crisis CML (bcCML) cells while sparing normal hematopoietic cells. Furthermore, analysis of progenitor cells using in vitro colony assays, as well as stem cells using the nonobese diabetic/severe combined immunodeficient (NOD/SCID) xenograft model, show that PTL also preferentially targets AML progenitor and stem cell populations. Notably, in comparison to the standard chemotherapy drug cytosine arabinoside (Ara-C), PTL is much more specific to leukemia cells. The molecular mechanism of PTL-mediated apoptosis is strongly associated with inhibition of nuclear factor kappa B (NF-kappa B), proapoptotic activation of p53, and increased reactive oxygen species (ROS). On the basis of these findings, we propose that the activity of PTL triggers LSC-specific apoptosis and as such represents a potentially important new class of drugs for LSC-targeted therapy.