title: Dual function of RGD-modified VEGI-192 for breast cancer treatment.
abstract: Identification of endogenous angiogenesis inhibitors has led to development of an increasingly attractive strategy for cancer therapy and other angiogenesis-driven diseases. Vascular endothelial growth inhibitor (VEGI), a potent and relatively nontoxic endogenous angiogenesis inhibitor, has been intensively studied, and this work shed new light on developing promising anti-angiogenic strategies. It is well-documented that the RGD (Arg-Gly-Asp) motif exhibits high binding affinity to integrin α(v)β(3), which is abundantly expressed in cancer cells and specifically associated with angiogenesis on tumors. Here, we designed a fusion protein containing the special RGD-4C motif sequence and VEGI-192, aimed at offering more effective multiple targeting to tumor cells and tumor vasculature, and higher anti-angiogenic and antitumor efficacy. Functional tests demonstrated that the purified recombinant human RGD-VEGI-192 protein (rhRGD-VEGI-192) potently inhibited endothelial growth in vitro and suppressed neovascularization in chicken chorioallantoic membrane in vivo, to a higher degree as compared with rhVEGI-192 protein. More importantly, rhRGD-VEGI-192, but not rhVEGI-192 protein, could potentially target MDA-MB-435 breast tumor cells, significantly inhibiting growth of MDA-MB-435 cells in vitro, triggered apoptosis in MDA-MB-435 cells by activation of caspase-8 as well as caspase-3, which was mediated by activating the JNK signaling associated with upregulation of pro-apoptotic protein Puma, and consequently led to the observed significant antitumor effect in vivo against a human breast cancer xenograft. Our study indicated that the RGD-VEGI-192 fusion protein might represent a novel anti-angiogenic and antitumor strategy.
authors.affiliation: Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, 74 Zhongshan Road II, Guangzhou 510080, China.
authors.forename: Jueheng
authors.initials: J
authors.lastname: Wu
authors.forename: Yi
authors.initials: Y
authors.lastname: Jiang
authors.forename: Wan
authors.initials: W
authors.lastname: Yang
authors.forename: Zhenjian
authors.initials: Z
authors.lastname: He
authors.forename: Shiyu
authors.initials: S
authors.lastname: Meng
authors.forename: Qianhui
authors.initials: Q
authors.lastname: Zhang
authors.forename: Min
authors.initials: M
authors.lastname: Lin
authors.forename: Henan
authors.initials: H
authors.lastname: Zhang
authors.forename: Weifeng
authors.initials: W
authors.lastname: Li
authors.forename: Yaochao
authors.initials: Y
authors.lastname: Yang
authors.forename: Yiqun
authors.initials: Y
authors.lastname: Jia
authors.forename: Liang
authors.initials: L
authors.lastname: Qian
authors.forename: Dihan
authors.initials: D
authors.lastname: Lu
authors.forename: Wenjia
authors.initials: W
authors.lastname: Cai
authors.forename: Guotian
authors.initials: G
authors.lastname: Luo
authors.forename: Yesong
authors.initials: Y
authors.lastname: Wang
authors.forename: Xun
authors.initials: X
authors.lastname: Zhu
authors.forename: Mengfeng
authors.initials: M
authors.lastname: Li
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000098:blood supply* / Q000188:drug therapy* / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002645:Chickens; D049033:Chorioallantoic Membrane / Q000098:blood supply / Q000187:drug effects; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D009842:Oligopeptides / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15 / Q000378:metabolism* / Q000494:pharmacology* / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D009842:Oligopeptides; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15; C047981:arginyl-glycyl-aspartic acid; D048031:JNK Mitogen-Activated Protein Kinases