Newly synthesized quinazolinone HMJ-38 suppresses angiogenetic responses and triggers human umbilical vein endothelial cell apoptosis through p53-modulated Fas/death receptor signaling

被引:53
作者
Chiang, Jo-Hua [1 ]
Yang, Jai-Sing [2 ]
Lu, Chi-Cheng [1 ]
Hour, Mann-Jen [3 ]
Chang, Shu-Jen [3 ]
Lee, Tsung-Han [1 ,4 ]
Chung, Jing-Gung [4 ,5 ]
机构
[1] Natl Chung Hsing Univ, Dept Life Sci, Taichung 402, Taiwan
[2] China Med Univ, Dept Pharmacol, Taichung 404, Taiwan
[3] China Med Univ, Sch Pharm, Taichung 40402, Taiwan
[4] China Med Univ, Dept Biol Sci & Technol, Taichung 404, Taiwan
[5] Asia Univ, Dept Biotechnol, Taichung 413, Taiwan
关键词
HMJ-38; Angiogenesis; Apoptosis; Fas/death receptor; p53; Human umbilical vein endothelial cells; ENDOPLASMIC-RETICULUM STRESS; TRAIL-INDUCED APOPTOSIS; GROWTH IN-VIVO; CANCER-CELLS; TUMOR-GROWTH; UP-REGULATION; TUBULIN POLYMERIZATION; INHIBITS ANGIOGENESIS; DEPENDENT PATHWAYS; OXIDATIVE STRESS;
D O I
10.1016/j.taap.2013.03.007
中图分类号
R9 [药学];
学科分类号
100702 [药剂学];
摘要
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. (C) 2013 Elsevier Inc. All rights reserved.
引用
收藏
页码:150 / 162
页数:13
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