Arsenic Trioxide Suppresses Tumor Growth through Antiangiogenesis via Notch Signaling Blockade in Small-Cell Lung Cancer
Arsenic Trioxide Suppresses Tumor Growth through Antiangiogenesis via Notch Signaling Blockade in Small-Cell Lung Cancer
复制标题
三氧化二砷通过阻断小细胞肺癌中的 Notch 信号传导来抗血管生成，从而抑制肿瘤生长
DOI：
10.1155/2019/4647252
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发表时间：
2019
影响因子：
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通讯作者：
Chen Wan Sheng
中科院分区：
文献类型：
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作者：
Yang Meng Hang;Chang Ke Jie;Li Bing;Chen Wan Sheng
小细胞肺癌（SCLC）是一种高度恶性的肺癌，没有有效的二线化疗药物。据报道，三氧化二砷（As2O3）对肺癌具有抗血管生成活性，并诱导血管结构发育不良，类似于阻断Notch信号传导后观察到的效果。然而，As2O3通过阻断Notch信号通路抑制SCLC肿瘤生长和血管生成的作用尚缺乏直接证据。本研究发现，As_2O_3能显著抑制SCLC的肿瘤生长和血管生成，并降低微血管密度。As2O3可干扰肿瘤血管的形态发育，并下调体内δ样典型Notch配体4（Dll4）、Notch 1和Hes 1的蛋白水平。Notch信号抑制剂DAPT在SCLC中发挥类似作用。我们发现As2O3处理和Notch 1表达敲低均导致人脐静脉内皮细胞（HUVECs）在Matrigel上的小管形成中断。As2O3对人脐静脉内皮细胞中Dll4表达无影响，但显著抑制Notch 1及其下游基因Hes 1的表达。这些结果表明，As2O3在小细胞肺癌中的抗肿瘤活性是通过其通过阻断Notch信号传导的抗血管生成作用介导的，可能是由于Notch 1靶向。
Small‐cell lung cancer (SCLC) is a highly malignant type of lung cancer with no effective second‐line chemotherapy drugs. Arsenic trioxide (As2O3) was reported to exert antiangiogenesis activities against lung cancer and induce poor development of vessel structures, similar to the effect observed following the blockade of Notch signaling. However, there are no direct evidences on the inhibitory effects of As2O3on tumor growth and angiogenesis via blockade of Notch signaling in SCLC. Here, we found that As2O3significantly inhibited the tumor growth and angiogenesis in SCLC and reduced the microvessel density. As2O3disturbed the morphological development of tumor vessels and downregulated the protein levels of delta‐like canonical Notch ligand 4 (Dll4), Notch1, and Hes1in vivo. DAPT, a Notch signaling inhibitor, exerted similar effects in SCLC. We found that both As2O3treatment andNotch1expression knockdown resulted in the interruption of tube formation by human umbilical vein endothelial cells (HUVECs) on Matrigel. As2O3had no effects on Dll4 level in HUVECs but significantly inhibited the expression ofNotch1and its downstream geneHes1regardless of Dll4 overexpression or Notch1 knockdown. These findings suggest that the antitumor activity of As2O3in SCLC was mediated via its antiangiogenic effect through the blockade of Notch signaling, probably owing to Notch1 targeting.