Glipizide, an antidiabetic drug, suppresses tumor growth and metastasis by inhibiting angiogenesis
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Cuiling Qi1,*, Qin Zhou1,*, Bin Li1, Yang Yang1, Liu Cao4, Yuxiang Ye1, Jiangchao Li1, Yi Ding1, Huiping Wang1, Jintao Wang1, Xiaodong He1, Qianqian Zhang1, Tian Lan1, Kenneth Ka Ho Lee3, Weidong Li1, Xiaoyu Song4, Jia Zhou5, Xuesong Yang2 and Lijing Wang1
1 Vascular Biology Research Institute, Guangdong Pharmaceutical University, Guangzhou, China
2 Key Laboratory for Regenerative Medicine of the Ministry of Education, Division of Histology & Embryology, Medical College, Jinan University, Guangzhou, China
3 Key Laboratory for Regenerative Medicine of the Ministry of Education, School of Biomedical Sciences, Chinese University of Hong Kong, Shatin, Hong Kong, China
4 Key Laboratory of Medical Cell Biology, China Medical University, He Ping District, Shen Yang City, Liao Ning Province, China
5 Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, United States
* These authors contributed equally to this work
Lijing Wang, email:
Xuesong Yang, email:
Keywords: glipizide; anticancer; metastasis; tumor angiogenesis; natriuretic peptide receptor A
Received: July 18, 2014 Accepted: September 15, 2014 Published: September 16, 2014
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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