Antileukemia activity of the novel peptidic CXCR4 antagonist LY2510924 as monotherapy and in combination with chemotherapy
Antileukemia activity of the novel peptidic CXCR4 antagonist LY2510924 as monotherapy and in combination with chemotherapy
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DOI：
10.1182/blood-2015-02-628677
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发表时间：
2015-07-09
期刊：
影响因子：
20.3
通讯作者：
Konopleva, Marina
中科院分区：
文献类型：
--
作者：
Cho, Byung-Sik;Zeng, Zhihong;Konopleva, Marina
靶向基质细胞衍生因子1 α (SDF-1 α)/C-X-C趋化因子受体4型（CXCR4）轴已被证明是克服急性髓性白血病（AML）化疗耐药的一种有前景的治疗方法。我们研究了一种新型肽类CXCR4拮抗剂LY2510924在AML临床前模型中的抗白血病功效。LY2510924比小分子CXCR4拮抗剂AMD3100更有效地快速和持久地阻断表面CXCR4，并在纳米摩尔浓度下抑制基质细胞衍生因子1 (SDF-1) α诱导的AML细胞趋化和促生存信号。在体外，LY2510924主要抑制AML细胞的增殖，几乎不诱导细胞死亡，降低基质细胞对化疗的保护作用。在已确诊的AML小鼠中，LY2510924引起白血病细胞进入循环的初始动员，随后减少肿瘤总负荷。LY2510924单药及联合化疗均有抗白血病作用。从ly2510924处理的小鼠中分离的AML细胞的基因表达谱显示出与SDF-1 α / cxcr4信号丢失一致的变化，并表明增殖减少和诱导分化，这通过显示多种促生存途径（如PI3K/AKT， MAPK和β -catenin）和骨髓分化的衰减得到了证明。LY2510924有效破坏SDF-1 α /CXCR4轴可能在未来的临床应用中转化为有效的抗白血病治疗。
Targeting the stromal cell-derived factor 1 alpha (SDF-1 alpha)/C-X-C chemokine receptor type 4 (CXCR4) axis has been shown to be a promising therapeutic approach to overcome chemoresistance in acute myeloid leukemia (AML). We investigated the antileukemia efficacy of a novel peptidic CXCR4 antagonist, LY2510924, in preclinical models of AML. LY2510924 rapidly and durably blocked surface CXCR4 and inhibited stromal cell-derived factor 1 (SDF-1)alpha-induced chemotaxis and prosurvival signals of AML cells at nano-molar concentrations more effectively than the small-molecule CXCR4 antagonist AMD3100. In vitro, LY2510924 chiefly inhibited the proliferation of AML cells with little induction of cell death and reduced protection against chemotherapy by stromal cells. In mice with established AML, LY2510924 caused initial mobilization of leukemic cells into the circulation followed by reduction in total tumor burden. LY2510924 had antileukemia effects as monotherapy as well as in combination with chemotherapy. Gene expression profiling of AML cells isolated from LY2510924-treated mice demonstrated changes consistent with loss of SDF-1 alpha/CXCR4signaling and suggested reduced proliferation and induction of differentiation, which was proved by showing the attenuation of multiple prosurvival pathways such as PI3K/AKT, MAPK, and beta-catenin and myeloid differentiation in vivo. Effective disruption of the SDF-1 alpha/CXCR4 axis by LY2510924 may translate into effective antileukemia therapy in future clinical applications.