title: Glipizide, an antidiabetic drug, suppresses tumor growth and metastasis by inhibiting angiogenesis.
abstract: 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.
authors.affiliation: Vascular Biology Research Institute, Guangdong Pharmaceutical University, Guangzhou, China. These authors contributed equally to this work.
authors.forename: Cuiling
authors.initials: C
authors.lastname: Qi
authors.affiliation: Vascular Biology Research Institute, Guangdong Pharmaceutical University, Guangzhou, China. These authors contributed equally to this work.
authors.forename: Qin
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: Vascular Biology Research Institute, Guangdong Pharmaceutical University, Guangzhou, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.affiliation: Vascular Biology Research Institute, Guangdong Pharmaceutical University, Guangzhou, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Key Laboratory of Medical Cell Biology, China Medical University, He Ping District, Shen Yang City, Liao Ning Province, China.
authors.forename: Liu
authors.initials: L
authors.lastname: Cao
authors.affiliation: Vascular Biology Research Institute, Guangdong Pharmaceutical University, Guangzhou, China.
authors.forename: Yuxiang
authors.initials: Y
authors.lastname: Ye
authors.affiliation: Vascular Biology Research Institute, Guangdong Pharmaceutical University, Guangzhou, China.
authors.forename: Jiangchao
authors.initials: J
authors.lastname: Li
authors.affiliation: Vascular Biology Research Institute, Guangdong Pharmaceutical University, Guangzhou, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Vascular Biology Research Institute, Guangdong Pharmaceutical University, Guangzhou, China.
authors.forename: Huiping
authors.initials: H
authors.lastname: Wang
authors.affiliation: Vascular Biology Research Institute, Guangdong Pharmaceutical University, Guangzhou, China.
authors.forename: Jintao
authors.initials: J
authors.lastname: Wang
authors.affiliation: Vascular Biology Research Institute, Guangdong Pharmaceutical University, Guangzhou, China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: He
authors.affiliation: Vascular Biology Research Institute, Guangdong Pharmaceutical University, Guangzhou, China.
authors.forename: Qianqian
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Vascular Biology Research Institute, Guangdong Pharmaceutical University, Guangzhou, China.
authors.forename: Tian
authors.initials: T
authors.lastname: Lan
authors.affiliation: Key Laboratory for Regenerative Medicine of the Ministry of Education, School of Biomedical Sciences, Chinese University of Hong Kong, Shatin, Hong Kong, China.
authors.forename: Kenneth Ka Ho
authors.initials: KK
authors.lastname: Lee
authors.affiliation: Vascular Biology Research Institute, Guangdong Pharmaceutical University, Guangzhou, China.
authors.forename: Weidong
authors.initials: W
authors.lastname: Li
authors.affiliation: Key Laboratory of Medical Cell Biology, China Medical University, He Ping District, Shen Yang City, Liao Ning Province, China.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Song
authors.affiliation: Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, United States.
authors.forename: Jia
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Key Laboratory for Regenerative Medicine of the Ministry of Education, Division of Histology & Embryology, Medical College, Jinan University, Guangzhou, China.
authors.forename: Xuesong
authors.initials: X
authors.lastname: Yang
authors.affiliation: Vascular Biology Research Institute, Guangdong Pharmaceutical University, Guangzhou, China.
authors.forename: Lijing
authors.initials: L
authors.lastname: Wang
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000098:blood supply / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D005913:Glipizide / Q000494:pharmacology*; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D061986:MCF-7 Cells; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply / Q000188:drug therapy; D051379:Mice; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D007004:Hypoglycemic Agents; D005913:Glipizide