Anti-tumor effects of telmisartan in glioma-astrocyte non-contact co-cultures: A critical role of astrocytic IL-6-mediated paracrine growth promotion.

Autor: Quan W; Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China., Xu CS; Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China., Ma C; Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China., Chen X; Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China., Yu DH; Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China., Li ZY; Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China., Wang DW; Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China., Tang F; Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China., Wan GP; Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China., Wan J; Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China., Wang ZF; Department of Physiology, Wuhan University School of Basic Medical Sciences, Wuhan, Hubei, China. Electronic address: wangzf@whu.edu.cn., Li ZQ; Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China; Hubei International Science and Technology Cooperation Base for Research and Clinical Techniques for Brain Glioma Diagnosis and Treatment, Hubei, China. Electronic address: lizhiqiang@whu.edu.cn.
Jazyk: angličtina
Zdroj: International immunopharmacology [Int Immunopharmacol] 2024 Sep 30; Vol. 139, pp. 112707. Date of Electronic Publication: 2024 Jul 19.
DOI: 10.1016/j.intimp.2024.112707
Abstrakt: Telmisartan, an angiotensin II type 1 receptor (AT1R) blocker, exhibits broad anti-tumor activity. However, in vitro, anti-proliferative effects are shown at doses far beyond the therapeutic plasma concentration. Considering the role of tumor microenvironment in glioma progression, glioma-astrocyte co-cultures were employed to test the anti-tumor potential of low-dose telmisartan. When a high dose was required for a direct anti-proliferative effect on glioma cell lines, a low dose significantly inhibited glioma cell proliferation and migration in the co-culture system. Under co-culture conditions, upregulated IL-6 expression in astrocytes played a critical role in glioma progression. Silencing IL-6 in astrocytes or IL-6R in glioma cells reduced proliferation and migration. Telmisartan (5 μM) inhibited astrocytic IL-6 expression, and its anti-tumor effects were reversed by silencing IL-6 or IL-6R and inhibiting signal transducer and activator of transcription 3 (STAT3) activity in glioma cells. Moreover, the telmisartan-driven IL-6 downregulation was not imitated by losartan, an AT1R blocker with little capacity of peroxisome proliferator-activated receptor-gamma (PPARγ) activation, but was eliminated by a PPARγ antagonist, indicating that the anti-glioma effects of telmisartan rely on its PPARγ agonistic activity rather than AT1R blockade. This study highlights the importance of astrocytic IL-6-mediated paracrine signaling in glioma growth and the potential of telmisartan as an adjuvant therapy for patients with glioma, especially those with hypertension.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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