Abstract：
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.
摘要：
替米沙坦,血管紧张素II1型受体（AT1R）阻滞剂，具有广泛的抗肿瘤活性。然而,在体外，在远远超过治疗血浆浓度的剂量下显示抗增殖作用。考虑到肿瘤微环境在胶质瘤进展中的作用，神经胶质瘤-星形胶质细胞共培养用于测试低剂量替米沙坦的抗肿瘤潜力。当需要高剂量对神经胶质瘤细胞系的直接抗增殖作用时，低剂量可显著抑制共培养系统中神经胶质瘤细胞的增殖和迁移。在共培养条件下，IL-6在星形胶质细胞中的表达上调在神经胶质瘤的进展中起关键作用。沉默星形胶质细胞中的IL-6或胶质瘤细胞中的IL-6R会降低增殖和迁移。替米沙坦（5μM）抑制星形胶质细胞IL-6表达，通过沉默IL-6或IL-6R并抑制神经胶质瘤细胞中的信号转导和转录激活因子3（STAT3）活性来逆转其抗肿瘤作用。此外，替米沙坦驱动的IL-6下调没有被氯沙坦模仿，一种AT1R阻断剂，具有很少的过氧化物酶体增殖物激活受体γ（PPARγ）激活能力，但被PPARγ拮抗剂消除，这表明替米沙坦的抗胶质瘤作用依赖于其PPARγ激动活性而不是AT1R阻断。这项研究强调了星形细胞IL-6介导的旁分泌信号在胶质瘤生长中的重要性，以及替米沙坦作为胶质瘤患者辅助治疗的潜力，尤其是高血压患者.
