Glipizide, an antidiabetic drug, suppresses tumor growth and metastasis by inhibiting angiogenesis.
Glipizide, an antidiabetic drug, suppresses tumor growth and metastasis by inhibiting angiogenesis.
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格列吡嗪是一种抗糖尿病药物，通过抑制血管生成来抑制肿瘤生长和转移
DOI：
10.18632/oncotarget.2483
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发表时间：
2014-10-30
期刊：
影响因子：
--
通讯作者：
Wang L
中科院分区：
文献类型：
--
作者：
Qi C;Zhou Q;Li B;Yang Y;Cao L;Ye Y;Li J;Ding Y;Wang H;Wang J;He X;Zhang Q;Lan T;Lee KK;Li W;Song X;Zhou J;Yang X;Wang L
血管生成参与了多种人类癌症的发生、发展和转移。在此，我们报道了一种广泛用于治疗2型糖尿病的药物格列吡嗪的发现，它通过抑制肿瘤血管生成而成为一种有前途的抗癌药物。通过利用我们的体内鸡胚绒毛尿囊膜(CAM)和卵黄囊膜(YSM)模型对FDA批准的药库进行高通量筛选(HTS)，已证实格列吡嗪显著抑制血管形成和发育。此外，在异种移植瘤和MMTV-PYMT转基因小鼠模型上，发现格列吡嗪能抑制肿瘤血管生成、肿瘤生长和转移。我们进一步揭示，格列吡嗪的抗癌能力并不归因于其抗增殖作用，这些作用对各种人类癌细胞株并不显著。为了探讨其抗癌作用是否与应用格列吡嗪引起的血糖水平变化有关，另一种中长效磺脲类降糖药格列美脲以相同的方式进行了比较研究。有趣的是，格列美脲对肿瘤的生长和转移没有明显的影响，这表明格列吡嗪的抗癌作用并不是归因于它的抗糖尿病特性。此外，格列吡嗪通过上调钠尿肽受体A的表达抑制内皮细胞迁移和管状结构的形成，从而抑制血管生成。这些发现揭示了格列吡嗪作为一种潜在的癌症治疗的新机制，也首次提供了直接证据支持格列吡嗪治疗可以降低糖尿病患者的癌症风险。
Angiogenesis is involved in the development, progression and metastasis of various human cancers. Herein, we report the discovery of glipizide, a widely used drug for type 2 diabetes mellitus, as a promising anticancer agent through the inhibition of tumor angiogenesis. By high-throughput screening (HTS) of an FDA approved drug library utilizing our in vivo chick embryo chorioallantoic membrane (CAM) and yolk sac membrane (YSM) models, glipizide has been identified to significantly inhibit blood vessel formation and development. Moreover, glipizide was found to suppress tumor angiogenesis, tumor growth and metastasis using xenograft tumor and MMTV-PyMT transgenic mouse models. We further revealed that the anticancer capability of glipizide is not attributed to its antiproliferative effects, which are not significant against various human cancer cell lines. To investigate whether its anticancer efficacy is associated with the glucose level alteration induced by glipizide application, glimepiride, another medium to long-acting sulfonylurea antidiabetic drug in the same class, was employed for the comparison studies in the same fashion. Interestingly, glimepiride has demonstrated no significant impact on the tumor growth and metastasis, indicating that the anticancer effects of glipizide is not ascribed to its antidiabetic properties. Furthermore, glipizide suppresses endothelial cell migration and the formation of tubular structures, thereby inhibiting angiogenesis by up-regulating the expression of natriuretic peptide receptor A. These findings uncover a novel mechanism of glipizide as a potential cancer therapy, and also for the first time, provide direct evidence to support that treatment with glipizide may reduce the cancer risk for diabetic patients.
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影响因子：
17.3
作者：
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通讯作者：
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