Wogonoside impedes the progression of acute myeloid leukemia through inhibiting bone marrow angiogenesis
Wogonoside impedes the progression of acute myeloid leukemia through inhibiting bone marrow angiogenesis
复制标题
汉黄芩苷通过抑制骨髓血管生成阻止急性髓系白血病的进展
DOI：
10.1002/jcp.27067
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发表时间：
2019-02-01
影响因子：
5.6
通讯作者：
Lu, Na
中科院分区：
文献类型：
--
作者：
Lin, Binyan;Zhao, Kai;Lu, Na
降低骨髓（BM）微血管密度和循环血管生成细胞因子水平是治疗复发和耐药急性髓细胞白血病（AML）的有希望的策略。以往研究报道汉黄芩苷具有抑制AML进展和抑制实体瘤血管生成的作用，但这两种作用之间的相关性被忽略。在这项研究中，我们确定了汉黄芩苷是否可以抑制这种血液恶性肿瘤的血管生成。结果表明汉黄芩苷能抑制U937/MDR裸鼠移植瘤的生长和发展，延长其生存期。此外，减少骨髓血管生成可能会对耐药AML产生治疗作用。因此，建立了AML细胞和BM基质细胞之间的共培养以模拟它们的串扰。然后，在体外和体内检测汉黄芩苷对骨髓血管生成的影响。我们发现汉黄芩苷可以抑制鸡胚绒毛尿囊膜模型和基质胶塞试验中的微血管形成。机制研究表明汉黄芩苷可阻断AML细胞和间质细胞JAK 2-STAT 3通路，阻断其正反馈作用。我们检测了几种与AML或血管生成相关的细胞因子，发现分泌的白细胞介素-8是诱导骨髓血管生成的重要血管生成细胞因子。这些发现支持了在复发和耐药AML患者中可以开发新的诊断方法和有前景的治疗策略。
Decreasing bone marrow (BM) microvessel density and circulating angiogenic cytokine levels are promising strategies for the treatment of relapsed and resistant acute myeloid leukemia (AML). Previous studies have reported that wogonoside could inhibit the progression of AML and suppress angiogenesis in a solid tumor, but the correlation of these two effects was ignored. In this research, we determined whether wogonoside could inhibit angiogenesis in this hematologic malignancy. We found that wogonoside could inhibit tumor growth and progression, and prolong the survival of nude mice inoculated with U937/MDR. Besides, reducing BM angiogenesis might cause therapeutic effect against resistant AML. Therefore, coculture between AML cells and BM stromal cells was established to imitate their crosstalk. Then, the effect of wogonoside on BM angiogenesis was tested in vitro and in vivo. We found that wogonoside could suppress microvessel formation in the chicken chorioallantoic membrane assay model and matrigel plug assay. The mechanism research revealed that wogonoside could block the JAK2-STAT3 pathway in AML cells and stromal cells to break their positive feedback. We detected several cytokines related to AML or angiogenesis and found that secreted interleukin-8 was a significant angiogenic cytokine to induce BM angiogenesis. These findings supported that new diagnostics and promising treatment strategies could be developed in relapsed and resistant AML patients.