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

  • Authors:
    • 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
  • View Affiliations

  • Published online on: June 12, 2014     https://doi.org/10.3892/or.2014.3250
  • Pages: 597-606
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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.
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August-2014
Volume 32 Issue 2

Print ISSN: 1021-335X
Online ISSN:1791-2431

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Spandidos Publications style
Lu C, Chen H, Chiang J, Jin Y, Kuo S, Wu T, Hour M, Yang J and Chiu Y: Quinazoline analog HMJ-30 inhibits angiogenesis: Involvement of endothelial cell apoptosis through ROS-JNK-mediated death receptor 5 signaling. Oncol Rep 32: 597-606, 2014.
APA
Lu, C., Chen, H., Chiang, J., Jin, Y., Kuo, S., Wu, T. ... Chiu, Y. (2014). Quinazoline analog HMJ-30 inhibits angiogenesis: Involvement of endothelial cell apoptosis through ROS-JNK-mediated death receptor 5 signaling. Oncology Reports, 32, 597-606. https://doi.org/10.3892/or.2014.3250
MLA
Lu, C., Chen, H., Chiang, J., Jin, Y., Kuo, S., Wu, T., Hour, M., Yang, J., Chiu, Y."Quinazoline analog HMJ-30 inhibits angiogenesis: Involvement of endothelial cell apoptosis through ROS-JNK-mediated death receptor 5 signaling". Oncology Reports 32.2 (2014): 597-606.
Chicago
Lu, C., Chen, H., Chiang, J., Jin, Y., Kuo, S., Wu, T., Hour, M., Yang, J., Chiu, Y."Quinazoline analog HMJ-30 inhibits angiogenesis: Involvement of endothelial cell apoptosis through ROS-JNK-mediated death receptor 5 signaling". Oncology Reports 32, no. 2 (2014): 597-606. https://doi.org/10.3892/or.2014.3250