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Isolinderalactone suppresses human glioblastoma growth and angiogenic activity in 3D microfluidic chip and in vivo mouse models.
- Source :
-
Cancer letters [Cancer Lett] 2020 May 28; Vol. 478, pp. 71-81. Date of Electronic Publication: 2020 Mar 12. - Publication Year :
- 2020
-
Abstract
- Glioblastoma multiforme (GBM) is a lethal and highly vascular type of brain tumor. We previously reported that isolinderalactone enhances GBM apoptosis in vitro and in vivo, but its role in tumor angiogenesis is unknown. Here, we investigated the anti-angiogenic activity of isolinderalactone and its mechanisms. In a human GBM xenograft mouse model, isolinderalactone significantly reduced tumor growth and vessels. Isolinderalactone decreased the expression of vascular endothelial growth factor (VEGF) mRNA, protein, and VEGF secretion in hypoxic U-87 GBM cells and also in xenograft GMB tissue. In addition, we demonstrated that isolinderalactone significantly inhibited the proliferation, migration, and capillary-like tube formation of human brain microvascular endothelial cells (HBMECs) in the presence of VEGF. We also found that isolinderalactone decreased sprout diameter and length in a 3D microfluidic chip, and strongly reduced VEGF-triggered angiogenesis in vivo Matrigel plug assay. Isolinderalactone downregulated hypoxia-inducible factor-1α (HIF-1α) and HIF-2α proteins, decreased luciferase activity driven by the VEGF promoter in U-87 cells under hypoxic conditions, and suppressed VEGF-driven phosphorylation of VEGFR2 in HBMECs. Taken together, our results suggest that isolinderalactone is a promising candidate for GBM treatment through tumor angiogenesis inhibition.<br />Competing Interests: Declaration of competing interest The authors declare no competing financial interests.<br /> (Copyright © 2020 Elsevier B.V. All rights reserved.)
- Subjects :
- Angiogenesis Inhibitors pharmacology
Animals
Basic Helix-Loop-Helix Transcription Factors metabolism
Brain Neoplasms genetics
Brain Neoplasms metabolism
Cell Hypoxia drug effects
Cell Line, Tumor
Cell Proliferation drug effects
Cell Survival drug effects
Down-Regulation
Endothelial Cells cytology
Endothelial Cells drug effects
Endothelial Cells metabolism
Gene Expression Regulation, Neoplastic drug effects
Glioblastoma genetics
Glioblastoma metabolism
Humans
Hypoxia-Inducible Factor 1, alpha Subunit metabolism
Lab-On-A-Chip Devices
Male
Mice
Sesquiterpenes pharmacology
Signal Transduction drug effects
Xenograft Model Antitumor Assays
Angiogenesis Inhibitors administration & dosage
Brain Neoplasms drug therapy
Glioblastoma drug therapy
Sesquiterpenes administration & dosage
Vascular Endothelial Growth Factor A genetics
Vascular Endothelial Growth Factor A metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1872-7980
- Volume :
- 478
- Database :
- MEDLINE
- Journal :
- Cancer letters
- Publication Type :
- Academic Journal
- Accession number :
- 32173479
- Full Text :
- https://doi.org/10.1016/j.canlet.2020.03.009