Inhibition of CXCR4 with the novel RCP168 peptide overcomes stroma-mediated chemoresistance in chronic and acute leukemias
Inhibition of CXCR4 with the novel RCP168 peptide overcomes stroma-mediated chemoresistance in chronic and acute leukemias
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DOI：
10.1158/1535-7163.mct-06-0228
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发表时间：
2006-12-01
影响因子：
5.7
通讯作者：
Konopleva, Marina
中科院分区：
文献类型：
--
作者：
Zeng, Zhihong;Samudio, Ismael J.;Konopleva, Marina
趋化因子受体CXCR 4介导造血细胞迁移到基质衍生因子批次（SDF-1 α）产生的骨髓微环境。使用基于肽的CXCR 4抑制剂来自趋化因子病毒巨噬细胞炎性蛋白11，我们测试的假设，抑制CXCR 4增加化疗的敏感性，通过干扰基质/白血病细胞的相互作用。首先，检测表达不同量的表面CXCR 4的白血病细胞对单独或存在不同CXCR 4抑制剂的SDF-1 α或基质细胞的趋化反应。结果显示，多肽RCP 168对SDF-1 α或基质细胞诱导的白血病细胞的趋化性具有最强的拮抗作用。此外，RCP 168以浓度依赖性方式阻断抗CXCR 4单克隆抗体12 G5与表面CXCR 4的结合，并抑制SDF-1 α诱导的AKT和细胞外信号I调节的激酶磷酸化。最后，RCP 168显着增强化疗诱导的细胞凋亡基质共培养的Jurkat，原发性慢性淋巴细胞白血病，并在一个子集的急性髓性白血病细胞携带Flt 3突变。使用小分子CXCR 4抑制剂AMD 3465获得了相同的结果。因此，我们的数据表明，SDF-1 α/CXCR 4相互作用有助于白血病细胞对化疗诱导的凋亡的抵抗。通过肽CXCR 4抑制剂RCP 168破坏这些相互作用代表了靶向骨髓微环境中白血病细胞的新策略。
The chemokine receptor CXCR4 mediates the migration of hematopoietic cells to the stroma-derived factor lot (SDF-1 alpha)-producing bone marrow microenvironment. Using peptide-based CXCR4 inhibitors derived from the chemokine viral macrophage inflammatory protein 11, we tested the hypothesis that the inhibition of CXCR4 increases sensitivity to chemotherapy by interfering with stromal/leukemia cell interactions. First, leukemic cells expressing varying amounts of surface CXCR4 were examined for their chemotactic response to SDF-1 alpha or stromal cells, alone or in the presence of different CXCR4 inhibitors. Results showed that the polypeptide RCP168 had the strongest antagonistic effect on the SDF-1 alpha- or stromal cell-induced chemotaxis of leukemic cells. Furthermore, RCP168 blocked the binding of anti-CXCR4 monoclonal antibody 12G5 to surface CXCR4 in a concentration-dependent manner and inhibited SDF-1 alpha-induced AKT and extracellular signa I-regulated kinase phosphorylation. Finally, RCP168 significantly enhanced chemotherapy-induced apoptosis in stroma-cocultured Jurkat, primary chronic lymphocytic leukemia, and in a subset of acute myelogenous leukemia cells harboring Flt3 mutation. Equivalent results were obtained with the small-molecule CXCR4 inhibitor AMD3465. Our data therefore suggest that the SDF-1 alpha/CXCR4 interaction contributes to the resistance of leukemia cells to chemotherapy-induced apoptosis. Disruption of these interactions by the peptide CXCR4 inhibitor RCP168 represents a novel strategy for targeting leukemic cells within the bone marrow microenvironment.