Inhibition of the angiotensin II type 2 receptor AT2R is a novel therapeutic strategy for glioblastoma

被引：10

作者：

Perryman, Richard ^{[1
]}

Renziehausen, Alexander ^{[1
]}

Shaye, Hamidreza ^{[2
,3
]}

Kostagianni, Androniki D. ^{[4
]}

Tsiailanis, Antonis D. ^{[4
]}

Thorne, Thomas ^{[5
]}

Chatziathanasiadou, Maria, V ^{[1
,4
]}

Sivolapenko, Gregory B. ^{[6
]}

El Mubarak, Mohamed Ahmed ^{[6
]}

Han, Gye Won ^{[3
]}

Zarzycka, Barbara ^{[3
,7
]}

Katritch, Vsevolod ^{[3
,8
]}

Lebon, Guillaume ^{[9
]}

Lo Nigro, Cristiana ^{[10
]}

Lattanzio, Laura ^{[10
]}

Morse, Sophie, V ^{[1
,11
]}

Choi, James J. ^{[11
]}

O'Neill, Kevin ^{[1
,12
]}

Kanaki, Zoi ^{[13
]}

Klinakis, Apostolos ^{[13
]}

Crook, Tim ^{[1
]}

Cherezov, Vadim ^{[2
,3
]}

Tzakos, Andreas G. ^{[4
,14
,15
]}

Syed, Nelofer ^{[1
]}

机构：

[1] Imperial Coll, Dept Brain Sci, John Fulcher Mol Neurooncol Lab, London, England

[2] Univ Southern Calif, Dept Chem, Los Angeles, CA 90089 USA

[3] Univ Southern Calif, Bridge Inst, Los Angeles, CA 90089 USA

[4] Univ Ioannina, Dept Chem, Ioannina, Greece

[5] Univ Surrey, Dept Comp Sci, Guildford, Surrey, England

[6] Univ Patras, Dept Pharm, Lab Pharmacokinet, Patras, Greece

[7] Vrije Univ Amsterdam, Amsterdam Inst Mol Med & Syst, Div Med Chem, NL-1081 HZ Amsterdam, Netherlands

[8] Univ Southern Calif, Dept Quantitat & Computat Biol, Los Angeles, CA 90089 USA

[9] Univ Montpellier, Inst Genom Fonct, INSERM, CNRS, Montpellier, France

[10] Osped San Croce & Carle, Dept Oncol, Cuneo, Italy

[11] Imperial Coll London, Dept Bioengn, London, England

[12] Charing Cross Hosp, Dept Neurosurg, London, England

[13] Biomed Res Fdn Acad Athens, Ctr Basic Res, Athens, Greece

[14] Univ Res Ctr Ioannina, Inst Mat Sci & Comp, Ioannina, Greece

[15] Univ Ioannina, Biomed & Analyt Ctr BAC, Ioannina, Greece

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2022年 / 119卷 / 32期

基金：

荷兰研究理事会;

关键词：

glioblastoma; renin angiotensin system; angiotensin II; NEUROPATHIC PAIN; SYSTEM; SELECTIVITY; DOXORUBICIN; DELIVERY; GROWTH;

D O I：

10.1073/pnas.2116289119

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Glioblastoma (GBM) is an aggressive malignant primary brain tumor with limited therapeutic options. We show that the angiotensin II (AngII) type 2 receptor (AT(2)R) is a therapeutic target for GBM and that AngII, endogenously produced in GBM cells, promotes proliferation through AT(2)R. We repurposed EMA401, an AT(2)R antagonist originally developed as a peripherally restricted analgesic, for GBM and showed that it inhibits the proliferation of AT(2)R-expressing GBM spheroids and blocks their invasiveness and angiogenic capacity. The crystal structure of AT(2)R bound to EMA401 was determined and revealed the receptor to be in an active-like conformation with helix-VIII blocking G-protein or beta-arrestin recruitment. The architecture and interactions of EMA401 in AT(2)R differ drastically from complexes of AT(2)R with other relevant compounds. To enhance central nervous system (CNS) penetration of EMA401, we exploited the crystal structure to design an angiopep-2-tethered EMA401 derivative, A3E. A3E exhibited enhanced CNS penetration, leading to reduced tumor volume, inhibition of proliferation, and increased levels of apoptosis in an orthotopic xenograft model of GBM.

引用

页数：12