Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, 361003, PR China; Key Laboratory of Xiamen for Diagnosis and Treatment of Hematological Malignancy, Xiamen, 361003, PR China.
State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, 361005, China.
Exp Cell Res. 2020 May 1;390(1):111934. doi: 10.1016/j.yexcr.2020.111934. Epub 2020 Feb 29.
Vascular permeability contributes to disease progression and drug resistance in hematological malignancies, including AML. Thus, targeting angiogenic signaling is a promising treatment strategy, especially for relapsed and resistant AML. The aim of this study was to evaluate the efficacy of apatinib, a novel receptor tyrosine kinase inhibitor that selectively targets VEGFR2.
Several AML cell lines were exposed to various concentrations of apatinib, and then CCK8 and Annexin V/PI assays were performed to determine IC50 values and apoptosis, respectively. The effect of apatinib against primary AML cells from 57 adult patients and 11 normal controls was also analyzed utilizing an apoptosis assay. Next, we tested the underlying mechanism of apatinib in AML using western blotting and mass cytometry (CyTOF). Finally, the activity of apatinib against tumor growth and angiogenesis was further evaluated in vivo in xenograft models.
We found apatinib significantly inhibited growth and promoted apoptosis in AML cell lines in vitro. Similarly, apatinib showed cytotoxicity against primary AML cells but didn't affect normal BMMCs. Its effect was highly correlated with several clinical features, such as NPM1 mutation, extramedullary infiltration, relapsed/refractory disease, and M2 and M5 FAB subtypes. In addition, apatinib suppressed AML growth and attenuated angiogenesis in xenograft models. Mechanistically, apatinib-induced cytotoxicity was closely associated with inhibition of the VEGFR2-mediated Src/STAT3 and AKT/mTOR pathways and induction of mitochondria-mediated apoptosis.
Apatinib exerts antileukemia effects by targeting VEGFR2-induced prosurvival signaling and angiogenesis, thus providing a rationale for the application of apatinib in AML.
血管通透性促进包括 AML 在内的血液系统恶性肿瘤的疾病进展和耐药性。因此，靶向血管生成信号是一种很有前途的治疗策略，特别是对于复发和耐药的 AML。本研究旨在评估新型受体酪氨酸激酶抑制剂阿帕替尼对 VEGFR2 的靶向作用，评估其在 AML 中的疗效。
将几种 AML 细胞系暴露于不同浓度的阿帕替尼中，然后通过 CCK8 和 Annexin V/PI 测定法分别确定 IC50 值和凋亡。还利用凋亡测定法分析了阿帕替尼对 57 名成年患者和 11 名正常对照者的原代 AML 细胞的作用。接下来，我们使用 Western blot 和液质联用技术（CyTOF）检测阿帕替尼在 AML 中的潜在作用机制。最后，在体内异种移植模型中进一步评估了阿帕替尼对肿瘤生长和血管生成的活性。
我们发现阿帕替尼在体外显著抑制 AML 细胞系的生长并促进凋亡。同样，阿帕替尼对原代 AML 细胞具有细胞毒性，但对正常 BMMCs 没有影响。其作用与多个临床特征高度相关，例如 NPM1 突变、髓外浸润、复发/难治性疾病以及 M2 和 M5 FAB 亚型。此外，阿帕替尼抑制了异种移植模型中的 AML 生长和血管生成。在机制上，阿帕替尼诱导的细胞毒性与抑制 VEGFR2 介导的 Src/STAT3 和 AKT/mTOR 通路以及诱导线粒体介导的凋亡密切相关。
阿帕替尼通过靶向 VEGFR2 诱导的生存信号和血管生成发挥抗白血病作用，为阿帕替尼在 AML 中的应用提供了依据。
