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

• Published in: International immunopharmacology 2024-09, Vol.139, p.112707, Article 112707
• Main Authors: Quan, Wei, Xu, Cheng-Shi, Ma, Chao, Chen, Xi, Yu, Dong-Hu, Li, Zhi-Yu, Wang, Dan-Wen, Tang, Feng, Wan, Gui-Ping, Wan, Jing, Wang, Ze-Fen, Li, Zhi-Qiang
• Format: Article
• Language: English
• Subjects: Angiotensin II Type 1 Receptor Blockers - pharmacology; Angiotensin II Type 1 Receptor Blockers - therapeutic use; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Astrocytes; Astrocytes - drug effects; Astrocytes - metabolism; Brain Neoplasms - drug therapy; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Cell Line, Tumor; Cell Movement - drug effects; Cell Proliferation - drug effects; Coculture Techniques; Glioma; Glioma - drug therapy; Glioma - metabolism; Glioma - pathology; Humans; IL-6; Interleukin-6 - metabolism; Losartan - pharmacology; Paracrine Communication - drug effects; PPAR gamma - metabolism; Proliferator-activated receptor γ; Receptors, Interleukin-6 - metabolism; STAT3 Transcription Factor - metabolism; Telmisartan; Telmisartan - pharmacology; Telmisartan - therapeutic use; Tumor Microenvironment - drug effects
• ISSN: 1567-5769; 1878-1705; 1878-1705
• DOI: 10.1016/j.intimp.2024.112707

[Display omitted] •Low-dose telmisartan inhibited glioma proliferation and migration in co-cultures.•Astrocyte-derived IL-6 promoted glioma cell proliferation and migration.•Telmisartan inhibits IL-6/STAT3 pathway between astrocyte and glioma.•Telmisartan exerts the anti-tumor effects via PPARγ activation. 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.