The Antiparasitic Drug, Potassium Antimony Tartrate, Inhibits Tumor Angiogenesis and Tumor Growth in Nonsmall-Cell Lung Cancer
The Antiparasitic Drug, Potassium Antimony Tartrate, Inhibits Tumor Angiogenesis and Tumor Growth in Nonsmall-Cell Lung Cancer
复制标题
抗寄生虫药酒石酸钾锑可抑制非小细胞肺癌的肿瘤血管生成和肿瘤生长
DOI：
10.1124/jpet.114.218644
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发表时间：
2015-01-01
影响因子：
3.5
通讯作者：
Pang, Xiufeng
中科院分区：
文献类型：
--
作者：
Wang, Beibei;Yu, Weiwei;Pang, Xiufeng
重新利用现有药物不仅加速了药物发现，而且迅速推进了临床治疗策略。在本文中，我们通过筛选美国食品和药物管理局批准的化学药物，将酒石酸锑钾（PAT）（一种抗寄生虫药物）确定为一种阻断血管生成的新型药物。通过比较 PAT 在各种非小细胞肺癌 (NSCLC) 细胞中的细胞毒性与在原代培养的人脐静脉内皮细胞 (HUVEC) 中观察到的细胞毒性，我们发现 HUVEC 对 PAT 治疗更加敏感。在由 PAT 抗性 A549 细胞或患者原发肿瘤建立的体内肿瘤异种移植小鼠模型中，PAT 在 40 mg/kg（腹腔注射，每日）剂量下显着降低了 NSCLC 异种移植物的肿瘤体积和肿瘤重量，更重要的是，增强了顺铂化疗的抗肿瘤功效。经处理的异种移植物中血管化的显着丧失表明 PAT 具有体内抗血管生成特性，这与其在 NSCLC 细胞中的肿瘤生长抑制作用密切相关。此外，在体外血管生成测定中，PAT 对不同刺激的 HUVEC 增殖、迁移和管形成表现出剂量依赖性抑制。一致地，PAT 还消除了基质胶塞测定中血管内皮细胞生长因子诱导的血管生成。从机制上讲，我们发现 PAT 抑制几种受体酪氨酸激酶的活性，并特异性阻断 HUVEC 中下游 Src 和粘着斑激酶的激活。总而言之，我们的结果表征了 PAT 在 NSCLC 细胞中的新型抗血管生成和抗肿瘤功能。可能有必要在抗癌临床试验中进一步研究 PAT。
Repurposing existing drugs not only accelerates drug discovery but rapidly advances clinical therapeutic strategies. In this article, we identified potassium antimonyl tartrate (PAT), an antiparasitic drug, as a novel agent to block angiogenesis by screening US Food and Drug Administration-approved chemical drugs. By comparing the cytotoxicity of PAT in various nonsmall-cell lung cancer (NSCLC) cells with that observed in primary cultured human umbilical vein endothelial cells (HUVECs), we found that HUVECs were much more sensitive to the PAT treatment. In in vivo tumor xenograft mouse models established either by PAT-resistant A549 cells or by patient primary tumors, PAT significantly decreased the tumor volume and tumor weight of NSCLC xenografts at dosage of 40 mg/kg (i.p., daily) and, more importantly, augmented the antitumor efficacy of cisplatin chemotherapy. Remarkable loss of vascularization in the treated xenografts indicated the in vivo antiangiogenesis property of PAT, which was well correlated with its tumor growth inhibition in NSCLC cells. Furthermore, in the in vitro angiogenic assays, PAT exhibited dose-dependent inhibition of HUVEC proliferation, migration, and tube formation in response to different stimuli. Consistently, PAT also abolished the vascular endothelial cell growth factor-induced angiogenesis in the Matrigel plugs assay. Mechanistically, we found that PAT inhibited the activities of several receptor tyrosine kinases and specifically blocked the activation of downstream Src and focal adhesion kinases in HUVECs. Taken together, our results characterized the novel antiangiogenic and antitumor function of PAT in NSCLC cells. Further study of PAT in anticancer clinical trials may be warranted.