title: Quinazoline analog HMJ-30 inhibits angiogenesis: involvement of endothelial cell apoptosis through ROS-JNK-mediated death receptor 5 signaling.
abstract: The aim of the present study was to explore the effect of 6-fluoro-2-(3-fluorophenyl)-4-(cyanoanilino) quinazoline (HMJ-30) on the anti-angiogenic properties and apoptosis-related mechanism of human umbilical vein endothelial cells (HUVECs). In this study, HMJ-30 dose- and time-dependently inhibited the viability of HUVECs. We also found that HMJ-30 enhanced disruption of tube-like structures and suppressed cell migration in HUVECs after vascular endothelial growth factor (VEGF) induction. HMJ-30 was also observed to inhibit vessel branching and sprouting in chicken chorioallantoic membrane (CAM). Microsprouting induced by VEGF in the rat aortic ring and blood vessel formation in a mouse Matrigel plug were individually suppressed by HMJ-30. In an in vitro study, HMJ-30 induced the apoptotic death of HUVECs as indicated by DNA fragmentation and promoted reactive oxygen species (ROS) production as determined by flow cytometric assay. In addition, extrinsic caspase signaling (caspase-8 and -3) was activated in the HMJ-30-treated HUVECs and their inhibitors were applied to assess the signal transduction. We investigated the upstream of the death receptor pathway and further observed that the levels of death receptor 5 (DR5) and phosphorylated c-Jun N-terminal kinase (JNK) signals were upregulated in HUVECs following HMJ-30 challenge, which was confirmed by a JNK-specific inhibitor (SP600125). Hence, HMJ-30-induced endothelial cell apoptosis involved the ROS/JNK-regulated DR5 pathway. In summary, HMJ-30 may provide a potential therapeutic effect for the anti-vascular targeting of angiogenesis during cancer treatment.
authors.affiliation: Department of Food Science and Biotechnology, National Chung Hsing University, Taichung 402, Taiwan, R.O.C.
authors.forename: Chi-Cheng
authors.initials: CC
authors.lastname: Lu
authors.affiliation: Department of Biochemistry, Tzu Chi University, Hualien 970, Taiwan, R.O.C.
authors.forename: Hao-Ping
authors.initials: HP
authors.lastname: Chen
authors.affiliation: Department of Chemistry, National Cheng Kung University, Tainan 701, Taiwan, R.O.C.
authors.forename: Jo-Hua
authors.initials: JH
authors.lastname: Chiang
authors.affiliation: Department of Dermatology, Taipei Medical University Hospital, Taipei 110, Taiwan, R.O.C.
authors.forename: Yi-An
authors.initials: YA
authors.lastname: Jin
authors.affiliation: Graduate Institute of Pharmaceutical Chemistry, China Medical University, Taichung 404, Taiwan, R.O.C.
authors.forename: Sheng-Chu
authors.initials: SC
authors.lastname: Kuo
authors.affiliation: Department of Chemistry, National Cheng Kung University, Tainan 701, Taiwan, R.O.C.
authors.forename: Tian-Shung
authors.initials: TS
authors.lastname: Wu
authors.affiliation: School of Pharmacy, China Medical University, Taichung 404, Taiwan, R.O.C.
authors.forename: Mann-Jen
authors.initials: MJ
authors.lastname: Hour
authors.affiliation: Department of Pharmacology, School of Medicine, China Medical University, Taichung 404, Taiwan, R.O.C.
authors.forename: Jai-Sing
authors.initials: JS
authors.lastname: Yang
authors.affiliation: Division of Reconstructive and Plastic Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei 112, Taiwan, R.O.C.
authors.forename: Yu-Jen
authors.initials: YJ
authors.lastname: Chiu
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D001011:Aorta / Q000166:cytology / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D002642:Chick Embryo; D004247:DNA / Q000032:analysis / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D051379:Mice; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D011799:Quinazolines / Q000008:administration & dosage* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: C560913:6-fluoro-2-(3-fluorophenyl)-4-(cyanoanilino)quinazoline; D020533:Angiogenesis Inhibitors; D000873:Anthracenes; D011799:Quinazolines; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D042461:Vascular Endothelial Growth Factor A; C432165:pyrazolanthrone; D004247:DNA