Department of Biological Science and Technology, China Medical University, Taichung, Taiwan.
Department of Radiation Oncology, Show Chwan Memorial Hospital, Changhua, Taiwan.
J Cell Mol Med. 2020 Apr;24(7):3982-4000. doi: 10.1111/jcmm.15022. Epub 2020 Mar 9.
Glioblastomas are the most aggressive type of brain tumour, with poor prognosis even after standard treatment such as surgical resection, temozolomide and radiation therapy. The overexpression of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in glioblastomas is recognized as an important treatment target. Thus, an urgent need regarding glioblastomas is the development of a new, suitable agent that may show potential for the inhibition of extracellular signal-regulated kinase (ERK)/NF-κB-mediated glioblastoma progression. Imipramine, a tricyclic antidepressant, has anti-inflammatory actions against inflamed glial cells; additionally, imipramine can induce glioblastoma toxicity via the activation of autophagy. However, whether imipramine can suppress glioblastoma progression via the induction of apoptosis and blockage of ERK/NF-κB signalling remains unclear. The main purpose of this study was to investigate the effects of imipramine on apoptotic signalling and ERK/NF-κB-mediated glioblastoma progression by using cell proliferation (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide [MTT] assay), flow cytometry, Western blotting, and cell invasion/migration assay analysis in vitro. The ERK and NF-κB inhibitory capacity of imipramine is detected by NF-κB reporter gene assay and Western blotting. Additionally, a glioblastoma-bearing animal model was used to validate the therapeutic efficacy and general toxicity of imipramine. Our results demonstrated that imipramine successfully triggered apoptosis through extrinsic/intrinsic pathways and suppressed the invasion/migration ability of glioblastoma cells. Furthermore, imipramine effectively suppressed glioblastoma progression in vivo via the inhibition of the ERK/NF-κB pathway. In summary, imipramine is a potential anti-glioblastoma drug which induces apoptosis and has the capacity to inhibit ERK/NF-κB signalling.
胶质母细胞瘤是最具侵袭性的脑肿瘤之一，即使在标准治疗（如手术切除、替莫唑胺和放射治疗）后，预后仍然很差。核因子-κB 轻链增强子的活化 B 细胞（NF-κB）在胶质母细胞瘤中的过度表达被认为是一个重要的治疗靶点。因此，迫切需要开发一种新的、合适的药物，可能对抑制细胞外信号调节激酶（ERK）/NF-κB 介导的胶质母细胞瘤进展具有潜在作用。丙咪嗪是一种三环抗抑郁药，具有抗炎作用，可以对抗炎症激活的神经胶质细胞；此外，丙咪嗪可以通过诱导自噬来诱导胶质母细胞瘤毒性。然而，丙咪嗪是否可以通过诱导细胞凋亡和阻断 ERK/NF-κB 信号通路来抑制胶质母细胞瘤的进展尚不清楚。本研究的主要目的是通过体外细胞增殖（3-（4,5-二甲基噻唑-2-基）-2,5-二苯基四唑溴盐[MTT]测定）、流式细胞术、Western blot 分析和细胞侵袭/迁移实验，研究丙咪嗪对凋亡信号和 ERK/NF-κB 介导的胶质母细胞瘤进展的影响。通过 NF-κB 报告基因测定和 Western blot 检测丙咪嗪对 ERK 和 NF-κB 的抑制能力。此外，还使用胶质母细胞瘤荷瘤动物模型验证了丙咪嗪的治疗效果和一般毒性。我们的研究结果表明，丙咪嗪通过外源性/内源性途径成功触发细胞凋亡，并抑制了胶质母细胞瘤细胞的侵袭/迁移能力。此外，丙咪嗪通过抑制 ERK/NF-κB 通路在体内有效抑制了胶质母细胞瘤的进展。总之，丙咪嗪是一种潜在的抗胶质母细胞瘤药物，可诱导细胞凋亡，并具有抑制 ERK/NF-κB 信号通路的能力。
