Apatinib exhibits anti-leukemia activity in preclinical models of acute lymphoblastic leukemia.
Apatinib exhibits anti-leukemia activity in preclinical models of acute lymphoblastic leukemia.
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阿帕替尼在急性淋巴细胞白血病临床前模型中表现出抗白血病活性
DOI：
10.1186/s12967-018-1421-y
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发表时间：
2018-02-28
影响因子：
7.4
通讯作者：
Xu B
中科院分区：
文献类型：
--
作者：
Deng M;Zha J;Jiang Z;Jia X;Shi Y;Li P;Chen XL;Fang Z;Du Z;Xu B
急性淋巴细胞白血病（ALL）是一种以未成熟B淋巴细胞或T淋巴细胞不受控制的增殖为特征的克隆性恶性疾病。广泛的研究表明血管生成信号参与ALL的进展和对治疗的抵抗。因此，用抗血管生成药物靶向血管生成可能是治疗ALL的一种很有前途的方法。在这项研究中，我们研究了Apatinib的有效性，Apatinib是一种新的受体酪氨酸激酶抑制剂，选择性靶向ALL细胞中的VEGFR-2。方法用不同浓度的阿帕替尼处理所有细胞系，分别采用CCK8法、流式细胞术检测ic50值和细胞凋亡。用流式细胞术分析了阿帕替尼对11例成人和正常人原发性ALL细胞的杀伤作用。接下来，我们采用western bolting and mass cytometry （CyTOF）方法探讨阿帕替尼细胞毒性的潜在机制。最后，在ALL的体内异种移植模型中进一步评估其抗白血病活性。结果阿帕替尼显著抑制B系和T系ALL细胞生长，促进细胞凋亡，并呈剂量依赖性和时间依赖性。阿帕替尼对Nalm6、Reh、Jurkat和Molt4的ic50值48 h分别为55.76±13.19、51.53±10.74、32.43±5.58、39.91±9.88 μmol/L， 72 h分别为30.34±2.65、31.96±3.92、17.62±5.90和17.65±2.17 μmol/L。同样，阿帕替尼对原代成人ALL细胞显示细胞毒活性，而对正常细胞则不影响。此外，在体内异种移植模型中，阿帕替尼抑制ALL的生长和进展。机制上，apatinib诱导的细胞毒性与VEGFR2及其下游信号级联的抑制密切相关，包括pi3k、MAPK和STAT3通路。结论我们的研究表明，阿帕替尼通过抑制VEGFR2信号通路诱导细胞凋亡发挥其抗白血病作用，支持阿帕替尼治疗ALL的潜在作用。
BackgroundAcute lymphoblastic leukemia (ALL) is a clonal malignant disorder characterized by an uncontrolled proliferation of immature B or T lymphocytes. Extensive studies have suggested an involvement of angiogenesis signaling in ALL progression and resistance to treatment. Thus, targeting angiogenesis with anti-angiogenic drugs may be a promising approach for ALL treatment. In this study, we investigated the effectiveness of Apatinib, a novel receptor tyrosine kinase inhibitor selectively targeting VEGFR-2 in ALL cells.MethodALL cell lines were treated with different concentration of Apatinib and then CCK8 assay, flow cytometry were used to determine the IC50value and cell apoptosis, respectively. The effect of Apatinib against primary ALL cells from 11 adult patients and normal counterparts were also analyzed by apoptosis with flow cytometry. Next, we used western bolting and mass cytometry (CyTOF) assay to explore the underlying mechanism of the cytotoxicity of Apatinib. Finally, the anti-leukemia activity was further evaluated in an in vivo xenograft model of ALL.ResultsOur results showed that Apatinib significantly inhibited cell growth and promoted apoptosis in both B and T lineage ALL cell lines in a dose- and time-dependent manner. The IC50values of Apatinib against Nalm6, Reh, Jurkat and Molt4 for 48 h were 55.76 ± 13.19, 51.53 ± 10.74, 32.43 ± 5.58, 39.91 ± 9.88 μmol/L, and for 72 h were 30.34 ± 2.65, 31.96 ± 3.92, 17.62 ± 5.90, and 17.65 ± 2.17 μmol/L respectively. Similarly, Apatinib shows cytotoxic activity against primary adult ALL cells while sparing their normal counterparts in vitro. Moreover, Apatinib suppressed ALL growth and progression in an in vivo xenograft model. Mechanistically, Apatinib-induced cytotoxicity was closely associated with inhibition of VEGFR2 and its downstream signaling cascades, including the PI3 K, MAPK and STAT3 pathways.ConclusionOur study indicates that Apatinib exerts its anti-leukemia effect by inducing apoptosis through suppressing the VEGFR2 signaling pathway, supporting a potential role for Apatinib in the treatment of ALL.
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影响因子：
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影响因子：
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作者：
Lin Y;Zhai E;Liao B;Xu L;Zhang X;Peng S;He Y;Cai S;Zeng Z;Chen M
通讯作者：
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影响因子：
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作者：
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