Quinazoline analog HMJ-30 inhibits angiogenesis: Involvement of endothelial cell apoptosis through ROS-JNK-mediated death receptor 5 signaling

Chi Cheng Lu, Hao Ping Chen, Jo Hua Chiang, Yi An Jin, Sheng Chu Kuo, Tian Shung Wu, Mann Jen Hour, Jai Sing Yang, Yu Jen Chiu

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)

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 apoptosisrelated 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.

Original languageEnglish
Pages (from-to)597-606
Number of pages10
JournalOncology Reports
Volume32
Issue number2
DOIs
Publication statusPublished - 2014 Aug

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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