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Abstract：
Lung cancer is the leading cause of cancer-related death worldwide, and ~85% of lung cancers are non-small cell lung cancer (NSCLC), which has a low 5-year overall survival rate and high mortality. Several therapeutic strategies have been developed, such as targeted therapy, immuno-oncotherapy and combination therapy. However, the low survival rate indicates the urgent need for new NSCLC treatments. Vasculogenic mimicry (VM) is an endothelial cell-free tumor blood supply system of aggressive and metastatic tumor cells present during tumor neovascularization. VM is clinically responsible for tumor metastasis and resistance, and is correlated with poor prognosis in NSCLC, making it a potential therapeutic target. In the present study, A549 cells formed glycoprotein-rich lined tubular structures, and transcript levels of VM-related genes were markedly upregulated in VM-forming cells. Based on a drug repurposing strategy, it was demonstrated that doxazosin (an antihypertensive drug) displayed inhibitory activity on VM formation at non-cytotoxic concentrations. Doxazosin significantly reduced the levels of vascular endothelial growth factor A (VEGF-A) and matrix metalloproteinase-2 (MMP-2) in the cell media during VM formation. Further experiments revealed that the protein expression levels of VEGF-A and vascular endothelial-cadherin (VE-cadherin), which contribute to tumor aggressiveness and VM formation, were downregulated following doxazosin treatment. Moreover, the downstream signaling Ephrin type-A receptor 2 (EphA2)/AKT/mTOR/MMP/Laminin-5γ2 network was inhibited in response to doxazosin treatment. In conclusion, the present study demonstrated that doxazosin displayed anti-VM activity in an NSCLC cell model through the downregulation of VEGF-A and VE-cadherin levels, and the suppression of signaling pathways related to the receptor tyrosine kinase, EphA2, protein kinases, AKT and mTOR, and proteases, MMP-2 and MMP-9. These results support the add-on anti-VM effect of doxazosin as a potential agent against NSCLC.
摘要：
肺癌是全球癌症相关死亡的主要原因，约85%的肺癌是非小细胞肺癌(NSCLC)，5年总生存率低，死亡率高。已经开发了几种治疗策略，比如靶向治疗,免疫肿瘤治疗和联合治疗。然而,低生存率表明迫切需要新的NSCLC治疗.血管生成拟态（VM）是在肿瘤新血管形成过程中存在的侵袭性和转移性肿瘤细胞的无内皮细胞肿瘤血液供应系统。VM在临床上负责肿瘤转移和耐药，并且与NSCLC的不良预后相关，使其成为潜在的治疗靶点。在本研究中,A549细胞形成富含糖蛋白的内衬管状结构，VM相关基因的转录水平在VM形成细胞中显著上调。基于药物再利用策略，研究表明,在非细胞毒性浓度下,多沙唑嗪(一种抗高血压药物)对VM形成显示抑制活性.在VM形成过程中，多沙唑嗪显着降低了细胞培养基中血管内皮生长因子A（VEGF-A）和基质金属蛋白酶2（MMP-2）的水平。进一步的实验表明，VEGF-A和血管内皮钙粘蛋白（VE-cadherin）的蛋白表达水平，这有助于肿瘤的侵袭性和VM的形成，在多沙唑嗪治疗后下调。此外，下游信号EphrinA型受体2(EphA2)/AKT/mTOR/MMP/层粘连蛋白-5γ2网络在多沙唑嗪治疗后受到抑制.总之,本研究表明，多沙唑嗪通过下调VEGF-A和VE-cadherin水平在NSCLC细胞模型中显示出抗VM活性，以及与受体酪氨酸激酶相关的信号通路的抑制，EphA2,蛋白激酶,AKT和mTOR,和蛋白酶，MMP-2和MMP-9。这些结果支持多沙唑嗪作为抗NSCLC的潜在药物的附加抗VM作用。
