聚醚类抗生素Narasin通过VEGFR2/c-MET信号途径的抑癌作用研究

Tumor metastasis is responsible for more than 90% of cancer-associated mortalities and represents a vital clinical challenge. Mounting evidence suggest that VEGFR2 and c-MET-mediated signaling pathways have being the most novel and important targets for molecular-targeted biotherapy and drug development. In our early studies, we found that one of the polyether antibiotics, salinomycin, suppressed the angiogenesis and growth of human gastric cancer through VEGF/VEGFR2-mediated STAT3 signaling pathway. Furthermore, we screened inhibitors from the FDA approved drug liabraies further by MTS, migration, tube formation and molecular docking assays. We found that another polyether antibiotics, Narasin, strongly inhibited cell proliferation, migration and capillary-like tube formation of primarily cultured human umbilical vascular endothelial cells (HUVECs) in vitro in a dose-dependent manner. Additionally, we also comfirmed Narasin has the ablility of reducing the migrated numbers of gastric cancer cells. Western blot and molecular docking analysis assays revealed that Narasin suppressed the phosphorylation and activation of VEGFR2 and c-MET kinase, with IC50 of 250 nmol/L, implying that Narasin may be one of efficient angiogenesis and tumor metastasis inhibitor. Therefore, through working on different platforms that are in vitro, ex vivo and in vivo models, we systematically investigated the biological activities of the compound on angiogenesis, growth and tumor metastasis of human gastroesophageal cancer. These findings may pave a way to better reveal the novel functions and its molecular basis for the anticancer action, and thus provide a scientific basis for molecular targeted therapy.

肿瘤转移是患者治疗失败、复发和死亡的首要原因。研究表明： VEGFR2/c-MET信号途径是介导肿瘤转移和复发的重要靶标。项目前期证实聚醚类抗生素盐霉素通过VEGFR2/STAT3信号通路抑制胃癌血管生成和肿瘤生长的新功能。现通过计算机软件蛋白对接法，细胞毒性试验，血管内皮成管和迁移划痕实验，以VEGFR2/c-MET为靶点对聚醚类抗生素及结构类似物进行筛选。初步发现聚醚类抗生素Narasin能有效阻断VEGFR2/c-MET的活化，并显著抑制体外VEGF诱导的血管内皮细胞增殖、成管和多种胃癌细胞的迁移，提示Narasin很可能具有抗血管生成和肿瘤转移的作用。课题组拟通过多水平的实验项目研究Narasin抑制胃/食管癌血管新生、生长和肿瘤转移的疗效及分子机制，以期阐明Narasin的抗癌新功能和新机制，为肿瘤个体化治疗提供科学依据，为研制具有我国自主知识产权的肿瘤生物治疗药物奠定理论基础。