title: Newly synthesized quinazolinone HMJ-38 suppresses angiogenetic responses and triggers human umbilical vein endothelial cell apoptosis through p53-modulated Fas/death receptor signaling.
abstract: The current study aims to investigate the antiangiogenic responses and apoptotic death of human umbilical vein endothelial cells (HUVECs) by a newly synthesized compound named 2-(3'-methoxyphenyl)-6-pyrrolidinyl-4-quinazolinone (HMJ-38). This work attempted to not only explore the effects of angiogenesis on in vivo and ex vivo studies but also hypothesize the implications for HUVECs (an ideal cell model for angiogenesis in vitro) and further undermined apoptotic experiments to verify the underlying molecular signaling by HMJ-38. Our results demonstrated that HMJ-38 significantly inhibited blood vessel growth and microvessel formation by the mouse Matrigel plug assay of angiogenesis, and the suppression of microsprouting from the rat aortic ring assay was observed after HMJ-38 exposure. In addition, HMJ-38 disrupted the tube formation and blocked the ability of HUVECs to migrate in response to VEGF. We also found that HMJ-38 triggered cell apoptosis of HUVECs in vitro. HMJ-38 concentration-dependently suppressed viability and induced apoptotic damage in HUVECs. HMJ-38-influenced HUVECs were performed by determining the oxidative stress (ROS production) and ATM/p53-modulated Fas and DR4/DR5 signals that were examined by flow cytometry, Western blotting, siRNA and real-time RT-PCR analyses, respectively. Our findings demonstrate that p53-regulated extrinsic pathway might fully contribute to HMJ-38-provoked apoptotic death in HUVECs. In view of these observations, we conclude that HMJ-38 reduces angiogenesis in vivo and ex vivo as well as induces apoptosis of HUVECs in vitro. Overall, HMJ-38 has a potent anti-neovascularization effect and could warrant being a vascular targeting agent in the future.
authors.affiliation: Department of Life Sciences, National Chung Hsing University, 250 Kuo-Kuang Road, Taichung 402, Taiwan.
authors.forename: Jo-Hua
authors.initials: JH
authors.lastname: Chiang
authors.forename: Jai-Sing
authors.initials: JS
authors.lastname: Yang
authors.forename: Chi-Cheng
authors.initials: CC
authors.lastname: Lu
authors.forename: Mann-Jen
authors.initials: MJ
authors.lastname: Hour
authors.forename: Shu-Jen
authors.initials: SJ
authors.lastname: Chang
authors.forename: Tsung-Han
authors.initials: TH
authors.lastname: Lee
authors.forename: Jing-Gung
authors.initials: JG
authors.lastname: Chung
mesh_terms: D000818:Animals; D001011:Aorta; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D003094:Collagen; D004338:Drug Combinations; D042783:Endothelial Cells / Q000187:drug effects* / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D007797:Laminin; D051379:Mice; D018919:Neovascularization, Physiologic / Q000187:drug effects; D011509:Proteoglycans; D011759:Pyrrolidines / Q000737:chemistry / Q000494:pharmacology*; D052999:Quinazolinones / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017382:Reactive Oxygen Species; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D014471:Umbilical Veins / Q000166:cytology*; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism*
chemical_list: C416653:2-(3'-methoxyphenyl)-6-pyrrolidinyl-4-quinazolinone; D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; D011759:Pyrrolidines; D052999:Quinazolinones; D017382:Reactive Oxygen Species; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; D016159:Tumor Suppressor Protein p53; D042461:Vascular Endothelial Growth Factor A; D019014:fas Receptor; C059485:matrigel; D003094:Collagen; D020169:Caspases