Downregulation of VEGFR2 signaling by cedrol abrogates VEGF‑driven angiogenesis and proliferation of glioblastoma cells through AKT/P70S6K and MAPK/ERK1/2 pathways

Chang,Kai-Fu; Liu,Che-Yu; Huang,Ya-Chih; Hsiao,Chih-Yen; Tsai,Nu-Man

doi:10.3892/ol.2023.13928

Downregulation of VEGFR2 signaling by cedrol abrogates VEGF‑driven angiogenesis and proliferation of glioblastoma cells through AKT/P70S6K and MAPK/ERK1/2 pathways

Authors:
- Kai-Fu Chang
- Che-Yu Liu
- Ya-Chih Huang
- Chih-Yen Hsiao
- Nu-Man Tsai
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Affiliations: Department of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung 40201, Taiwan, R.O.C., Division of Endocrinology and Metabolism, Department of Internal Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chia-Yi 60002, Taiwan, R.O.C., Division of Nephrology, Department of Internal Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chia-Yi 60002, Taiwan, R.O.C.
Published online on: June 22, 2023 https://doi.org/10.3892/ol.2023.13928
Article Number: 342
Copyright: © Chang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Cedrol is a sesquiterpene alcohol isolated from Cedrus atlantica, which has been traditionally used in aromatherapy and has anticancer, antibacterial and antihyperalgesic effects. One characteristic of glioblastoma (GB) is the overexpression of vascular endothelial growth factor (VEGF), which induces a high degree of angiogenesis. Although previous studies have reported that cedrol inhibits GB growth by inducing DNA damage, cell cycle arrest and apoptosis, its role in angiogenesis remains unclear. The aim of the present study was to investigate the effects of cedrol on VEGF‑induced angiogenesis of human umbilical vein endothelial cells (HUVECs). HUVECs were treated with 0‑112 µM cedrol and 20 ng/ml VEGF for 0‑24 h, and then anti‑angiogenic activation of cedrol was determined by MTT assay, wound healing assay, Boyden chamber assay, tube formation assay, semi‑quantitative reverse transcription‑PCR and western blotting. These results demonstrated that cedrol treatment inhibited VEGF‑induced cell proliferation, migration and invasion in HUVECs. Furthermore, cedrol prevented VEGF and DBTRG‑05MG GB cells from inducing capillary‑like tube formation in HUVECs and decreased the number of branch points formed. Moreover, cedrol downregulated the phosphorylation of VEGF receptor 2 (VEGFR2) and the expression levels of its downstream mediators AKT, ERK, VCAM‑1, ICAM‑1 and MMP‑9 in HUVECs and DBTRG‑05MG cells. Taken together, these results demonstrated that cedrol exerts anti‑angiogenic effects by blocking VEGFR2 signaling, and thus could be developed into health products or therapeutic agents for the prevention or treatment of cancer and angiogenesis‑related diseases in the future.

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