格列吡嗪激活心房利钠肽-钠尿肽受体1信号通路抑制肿瘤血管形成作用机制研究

Glipizide is a commonly used anti-diabetes medication in the clinical. The long-term therapy of glipizide is associated with reduced cancer risk, but the anti-tumor activity of glipizide is still unknown. Natriuretic peptides have been shown to inhibit tumor growth, ANP specifically binding to NPR1, a angiogenesis inhibitor, to synthesize cGMP. Tumor angiogenesis plays an important role in tumor growth, invasion and metastasis. Our previous study found that glipizide can inhibits angiogenesis in chick embryo, and also inhibits cell migration and tube formation of human vascular endothelial cells. It was also showed that glipizide can inhibits tumor growth, invasion and metastasis in xenograft tumor and spontaneous cancer mice. Meanwhile, glipizide can significantly upregulated the expression of NPR1. Our results found that ANP-NPR1 signal transduction pathway can also inhibits angiogenesis in chick embryo, and also inhibits cell migration and tube formation of human vascular endothelial cells. These results indicated above suggested that glipizide may inhibit tumor angiogenesis by targeting ANP-NPR1 signal transduction pathway. Our project will clarify the molecular mechanism of glipizide in the inhibition of tumor angiogenesis, and will provide the basis for investigate the new functions of glipizide and clinical treatment of tumor.

格列吡嗪是临床上常用降糖药，但其抗肿瘤作用尚未发现。利钠肽能够抑制肿瘤增殖，心房利钠肽（ANP）选择性结合钠尿肽受体1（NPR1），促进合成cGMP发挥功能。肿瘤血管生成对肿瘤生长、侵袭及转移起着重要作用。我们通过大规模筛药发现格列吡嗪能抑制鸡胚血管发生，进而发现能抑制人血管内皮细胞迁移及管腔形成；能够显著抑制黑色素瘤和乳腺癌移植瘤、自发乳腺癌和前列腺癌小鼠肿瘤的生长转移及血管生成；并且促进了血管发生抑制基因（NPR1）表达显著上调。进一步研究表明上调ANP-NPR1信号通路能够抑制鸡胚血岛的形成、血管内皮细胞迁移及管腔形成，格列吡嗪能够激活这一通路。以上结果提示格列吡嗪可能激活ANP-NPR1信号通路抑制肿瘤血管发生，从而抑制肿瘤发生、发展。本项目拟以基因工程小鼠、鸡胚血管发生等为研究体系，阐明格列吡嗪抑制肿瘤血管生成的分子机制，为探讨药物新作用和肿瘤临床治疗提供新的理论依据和分子靶点。

血管新生在各种人类恶性肿瘤的发生、发展及转移的过程中起了重要的作用。我们发现临床用来治疗2型糖尿病的药物格列吡嗪通过抑制肿瘤血管新生，进而抑制了肿瘤的生长和转移。我们对FDA通过的480中药物库进行了高通量筛选，发现格列吡嗪具有抑制鸡胚血管形成的作用。进一步研究发现格列吡嗪可以显著抑制血管的形成，并具有浓度和时间的依赖性。而且，格列吡嗪通过抑制血管形成，进而抑制了移植瘤、MMTV-PyMT自发乳腺癌小鼠及TRAMP自发前列腺癌小鼠的肿瘤的生长和转移。进一步研究发现格列吡嗪对肿瘤细胞增殖则没有明显影响。进一步研究发现格列吡嗪通过上调NPRA表达抑制了血管新生。这些结果表明格列吡嗪可以作为一个抗肿瘤的药物，也为服用格列吡嗪治疗糖尿病的病人患癌的几率降低提供了有利的证据。在本课题的资助下共发表SCI收录文章8篇，申请专利3项，其中2项已授权。

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