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

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

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

Oncol Lett. 2023 Jun 22;26(2):342. doi: 10.3892/ol.2023.13928. eCollection 2023 Aug.

Authors

Kai-Fu Chang¹, Che-Yu Liu², Ya-Chih Huang^{1

3}, Chih-Yen Hsiao⁴, Nu-Man Tsai^{1

5

6}

Affiliations

¹ Department of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung 40201, Taiwan, R.O.C.
² Division of Endocrinology and Metabolism, Department of Internal Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chia-Yi 60002, Taiwan, R.O.C.
³ Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan, R.O.C.
⁴ Division of Nephrology, Department of Internal Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chia-Yi 60002, Taiwan, R.O.C.
⁵ Clinical Laboratory, Chung Shan Medical University Hospital, Taichung 40201, Taiwan, R.O.C.
⁶ Department of Life-and-Death Studies, Nanhua University, Chiayi 62249, Taiwan, R.O.C.

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.

Keywords: anti-angiogenesis; cedrol; glioblastoma; human umbilical vein endothelial cells; vascular endothelial growth factor.

Grants and funding

The present study was supported by the Ministry of Science and Technology (grant nos. MOST 109-2320-B-040-012, MOST 110-2320-B-040-006 and MOST 111-2320-B-040-022), Taiwan, R.O.C.