Radiotherapy opens the blood-brain barrier and synergizes with anlotinib in treating glioblastoma

被引：18

作者：

Li, Pei-Jing ^{[1
,2
]}

Lai, Shu-Zhen ^{[3
]}

Jin, Ting ^{[1
]}

Ying, Hang-Jie ^{[4
]}

Chen, Ya-Mei ^{[4
]}

Zhang, Peng ^{[1
]}

Hang, Qing-Qing ^{[1
]}

Deng, Huan ^{[1
]}

Wang, Lei ^{[1
]}

Feng, Jian-Guo ^{[4
]}

Chen, Xiao-Zhong ^{[1
]}

Guo, Peng ^{[5
]}

Chen, Ming ^{[7
]}

Tian, Ye ^{[2
,8
]}

Chen, Yuan-Yuan ^{[6
,7
]}

机构：

[1] Chinese Acad Sci, Zhejiang Canc Hosp, Inst Basic Med & Canc IBMC, Dept Radiat Oncol,Key Lab Head & Neck Canc Transla, Hangzhou, Peoples R China

[2] Soochow Univ, Affiliated Hosp 2, Inst Radiotherapy & Oncol, Dept Radiotherapy & Oncol,Suzhou Key Lab Radiat On, Suzhou, Peoples R China

[3] Shantou Univ, Yuebei Peoples Hosp, Dept Radiat Oncol, Shaoguan, Peoples R China

[4] Chinese Acad Sci, Zhejiang Canc Hosp, Zhejiang Canc Inst, Inst Basic Med & Canc IBMC, Hangzhou, Peoples R China

[5] Chinese Acad Sci, Inst Canc & Basic Med IBMC, Hangzhou, Peoples R China

[6] Sun Yat sen Univ Canc Ctr, Collaborat Innovat Ctr Canc Med, Dept Radiat Oncol, State Key Lab Oncol South China, Guangzhou, Peoples R China

[7] Sun Yat sen Univ, Canc Ctr, Dept Radiat Oncol, Guangzhou 510060, Peoples R China

[8] Soochow Univ, Affiliated Hosp 2, Dept Radiotherapy & Oncol, Suzhou 215004, Peoples R China

来源：

RADIOTHERAPY AND ONCOLOGY | 2023年 / 183卷

基金：

中国国家自然科学基金;

关键词：

Glioblastoma; Blood-brain barrier; Radiation; Tyrosine kinase inhibitors; JAK; STAT3; TEMOZOLOMIDE; RADIATION; BEVACIZUMAB; RESISTANCE; HYPOXIA;

D O I：

10.1016/j.radonc.2023.109633

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Background: Glioblastoma (GBM) has a poor prognosis and lacks effective treatment. Anlotinib is a mul-titargeted receptor tyrosine kinase inhibitor (TKI) that may have anti-tumor activity in the central ner-vous system (CNS). This study aimed to determine the therapeutic value of radiotherapy combined with anlotinib in GBM via preclinical research.Methods: HPLC-MS/MS was used to assess the concentration of anlotinib in blood and brain samples. Cell proliferation assays, flow cytometry, and colony formation assays were performed in vitro. The potential value of anlotinib or in combination with radiotherapy for GBM treatment was estimated in vivo. Western blotting, immunohistochemistry, and immunofluorescent staining were performed to deter-mine the underlying mechanism.Results: Anlotinib effectively inactivated the JAK3/STAT3 pathway to inhibit growth and induce apoptosis in malignant glioma cells (MGCs) independent of MGMT expression. Meanwhile, anlotinib induces MGCs G2/M arrest and sensitizes MGCs to radiation. Radiation down-regulates claudin-5 and weakens the blood-brain barrier (BBB), which contributes to the increased distribution of anlotinib in the CNS by 1.0-2.9 times. Anlotinib restrains tumor growth (PCNA), inhibits tumor microvascular proliferation (CD31), and alleviated intratumor hypoxia (HIF 1a) in vivo. Anlotinib alone or in combination with radi-ation is effective and safe in vivo evaluation.Conclusions: We discovered that anlotinib, the original small molecule antiangiogenesis TKI, down-regulates JAK3/STAT3 axis with anti-cancer activity alone or in combination with radiation. Anlotinib combined with radiotherapy might be a promising treatment for newly diagnosed GBM in the clinic.(c) 2023 Elsevier B.V. All rights reserved. Radiotherapy and Oncology 183 (2023) 109633

引用

页数：11