Targeting acute myeloid leukemia with a proapoptotic peptide conjugated to a toll-like receptor 2-mediated cell-penetrating peptide
Targeting acute myeloid leukemia with a proapoptotic peptide conjugated to a toll-like receptor 2-mediated cell-penetrating peptide
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使用与 Toll 样受体 2 介导的细胞穿透肽缀合的促凋亡肽治疗急性髓系白血病
DOI：
10.1002/ijc.28382
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发表时间：
2014-02-01
影响因子：
6.4
通讯作者：
Hu, Zhuo-Wei
中科院分区：
文献类型：
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作者：
Li, Ke;Lv, Xiao-Xi;Hu, Zhuo-Wei
细胞穿透肽提供了一个独特的平台，以创造新一代的癌症治疗，提高疗效和降低毒性。在我们的研究中，在急性髓系白血病（AML）细胞中观察到Toll样受体2（TLR 2）的表达增强。使用生物淘选和选择性相互作用配体的快速分析（BRASIL）筛选噬菌体展示肽库鉴定了TLR 2结合肽基序Pep 2。我们表明，TLR 2结合肽基序的靶向和渗透到白血病细胞中的TLR 2依赖的方式。此外，由连接至程序性细胞死亡诱导序列D（KLAKLAK）2的TLR 2结合基序组成的合成嵌合肽在具有高TLR 2表达（TLR 2（高））的AML细胞中诱导凋亡，但在具有低TLR 2表达（TLR 2（低））的慢性髓性白血病（CML）细胞中不诱导凋亡。该嵌合肽的抗白血病活性在白血病患者样品和髓性白血病动物模型中得到证实，因为与TLR 2（低）CML NOD/SCID小鼠相比，在具有TLR 2（高）AML的小鼠中白血病的发展显著延迟。骨髓组织切片的TUNEL检测显示嵌合肽以TLR 2依赖的方式诱导白血病细胞凋亡。总之，我们的研究结果表明TLR 2是预防和治疗AML的潜在治疗靶点，而原型Pep 2-D（KLAKLAK）2是这种情况下有前途的候选药物。细胞穿透肽是一种很有前途的细胞内给药工具。在这项研究中，作者假设受体TLR 2在急性髓性白血病（AML）中发挥作用，然后鉴定了靶向TLR 2的CPP。当这种CPP与促凋亡序列连接时，它诱导了AML细胞的凋亡，并且还降低了AML小鼠模型的死亡率。这些发现表明，TLR 2是AML的潜在治疗靶点，作者描述了一种靶向TLR 2的嵌合CPP，可能代表一种有前途的候选药物。
Cell-penetrating peptides provide a unique platform to create a new generation of cancer therapeutics with enhanced efficacy and diminished toxicity. In our study, enhanced expression of toll-like receptor 2 (TLR2) was observed in acute myeloid leukemia (AML) cells. Screening of a phage display peptide library using Biopanning and Rapid Analysis of Selective Interactive Ligands (BRASIL) identified a TLR2-binding peptide motif, Pep2. We show that the TLR2-binding peptide motif targeted and penetrated into leukemia cells in a TLR2-dependent manner. Moreover, a synthetic, chimeric peptide composed of the TLR2-binding motif linked to a programmed cell death-inducing sequence, D(KLAKLAK)2, induced apoptosis in AML cells with high TLR2 expression (TLR2(high)) but not in chronic myeloid leukemia (CML) cells with low TLR2 expression (TLR2(low)). The antileukemia activity of this chimeric peptide was confirmed in leukemia patient samples and an animal model of myeloid leukemia, as the development of leukemia was significantly delayed in mice with TLR2(high) AML compared to TLR2(low) CML NOD/SCID mice. TUNEL assays on bone marrow tissue slices revealed that the chimerical peptide induced leukemia cell apoptosis in a TLR2-dependent manner. Together, our findings indicate that TLR2 is a potential therapeutic target for the prevention and treatment of AML, and the prototype, Pep2-D(KLAKLAK)2, is a promising drug candidate in this setting.What's new? Cell-penetrating peptides (CPPs) are a promising tool for intracellular drug delivery. In this study, the authors hypothesized that the receptor TLR2 plays a role in acute myeloid leukemia (AML), then identified a CPP that targets TLR2. When this CPP was linked to a pro-apoptotic sequence, it induced apoptosis in AML cells, and also reduced mortality in a mouse model of AML. These findings indicate that TLR2 is a potential therapeutic target in AML, and the authors describe a chimeric CPP targeting TLR2 that may represent a promising drug candidate.