Gamma-secretase inhibitor DAPT suppresses glioblastoma growth via uncoupling of tumor vessel density from vessel function

Yuhui Zou; Yiqun Cao; Zhijian Yue; Jianmin Liu

doi:10.1007/s10238-012-0203-8

Gamma-secretase inhibitor DAPT suppresses glioblastoma growth via uncoupling of tumor vessel density from vessel function

Clin Exp Med. 2013 Nov;13(4):271-8. doi: 10.1007/s10238-012-0203-8. Epub 2012 Jul 27.

Authors

Yuhui Zou¹, Yiqun Cao, Zhijian Yue, Jianmin Liu

Affiliation

¹ Department of Neurosurgery, Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai, 200433, People's Republic of China.

PMID: 22836313
DOI: 10.1007/s10238-012-0203-8

Abstract

The objective of the current study was to investigate the regulation of VEGF signaling and tumor angiogenesis by gamma-secretase inhibitor DAPT in glioblastoma. Effects of DAPT on VEGFR1, VEGFR2, endothelial cell proliferation and vessel function were evaluated using mouse microvascular endothelial H5V cell line and U87MG xenograft mouse models. We found that DAPT efficiently inhibited Notch signaling, increased VEGFR2 expression, but decreased VEGFR1 expression. DAPT treatment enhanced endothelial cell proliferation when used combined with VEGF, but exerted no effect if used alone. In U87MG xenograft mouse models, DAPT treatment increased tumor vessel density but compromised vessel function, as evidenced by poor perfusion and aggravated hypoxia. Therefore, DAPT treatment results in an uncoupling of tumor vessel density from vessel function and suppresses glioblastoma growth; disturbance of angiogenesis with DAPT presents a novel therapeutic approach for glioblastoma.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amyloid Precursor Protein Secretases / antagonists & inhibitors*
Animals
Antineoplastic Agents / pharmacology
Antineoplastic Agents / therapeutic use*
Cell Line, Tumor
Cell Proliferation / drug effects
Dipeptides / pharmacology
Dipeptides / therapeutic use*
Disease Models, Animal
Endothelial Cells / drug effects
Female
Glioblastoma / drug therapy*
Glioblastoma / pathology*
Mice
Mice, Inbred BALB C
Neovascularization, Pathologic / drug therapy*
Vascular Endothelial Growth Factor A / pharmacology
Vascular Endothelial Growth Factor A / therapeutic use
Vascular Endothelial Growth Factor Receptor-1 / metabolism
Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

Antineoplastic Agents
Dipeptides
N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factor Receptor-1
Vascular Endothelial Growth Factor Receptor-2
Amyloid Precursor Protein Secretases