Department of Neurosurgery, Ankara City State Hospital, Ankara, Turkey.
Neuroscience Research Center, Suleyman Demirel University, Isparta, Turkey; BSN Health, Analysis and Innovation Ltd., Isparta, Turkey.
Chem Biol Interact. 2022 May 25;359:109914. doi: 10.1016/j.cbi.2022.109914. Epub 2022 Apr 5.
Cisplatin (CiSP) induced-overload Ca entry results in the increase of mitochondrial oxidative stress and apoptosis in the cancer cell. TRPM2 cation channel is gated by the cytosolic ADP-ribose (ADPR) and reactive oxygen species (ROS). The high content of polyunsaturated fatty acid (PUFA) in the brain is a main target of ROS. Eicosapentaenoic acid (EPA) induces oxidant action via the enhance of PUFA content in the glioblastoma (DBTRG) cells. We hypothesized that a combination of CiSP and EPA may offer a potential therapy in the DBTRG cell by exerting the antitumor, oxidant, and apoptotic actions and stimulating Ca influx and TRPM2 activity. In the DBTRG cells, we induced four groups as control, EPA (30 μM for 24 h), CiSP (25 μM for 24 h), and CiSP + EPA. The CiSP-induced intracellular Ca responses to the TRPM2 activation were increased in the DBTRG cells from coming HO and ADPR. The responses were decreased in the cells by the inhibitions of TRPM2 (ACA and 2/APB) and PARP/1 (DPQ and PJ34). The incubation of EPA further increased the intracellular Ca responses, mitochondria function, and the generation of ROS in the DBTRGs. After the treatment of EPA, lipid peroxidation, apoptosis, cell death, caspase -3, -8, and -9 levels were further increased in the DBTRG, although the levels of glutathione, glutathione peroxidase, cell numbers, and cell viability were further decreased in the cells. In summary, anticancer, apoptotic, and oxidant actions of CiSP were further increased via the activation of TRPM2 channel in the DBTRGs by the treatment of EPA. Hence, TRPM2 stimulation via EPA could be used as an effective agent in the treatment of glioblastoma tumors with CiSP.
顺铂（CiSP）诱导的钙内流过载会导致癌细胞中线粒体氧化应激和凋亡增加。TRPM2 阳离子通道由细胞质 ADP-核糖（ADPR）和活性氧（ROS）门控。大脑中多不饱和脂肪酸（PUFA）含量高是 ROS 的主要靶点。二十碳五烯酸（EPA）通过增加神经胶质瘤（DBTRG）细胞中 PUFA 的含量诱导氧化剂作用。我们假设 CiSP 和 EPA 的联合治疗可能通过发挥抗肿瘤、氧化和凋亡作用，刺激 Ca 内流和 TRPM2 活性，为 DBTRG 细胞提供潜在的治疗方法。在 DBTRG 细胞中，我们诱导了四个组作为对照、EPA（30 μM，24 h）、CiSP（25 μM，24 h）和 CiSP+EPA。CiSP 诱导的细胞内 Ca 反应通过 TRPM2 激活增加了来自 HO 和 ADPR 的 DBTRG 细胞。通过抑制 TRPM2（ACA 和 2/APB）和 PARP/1（DPQ 和 PJ34），反应在细胞中减少。EPA 的孵育进一步增加了 DBTRGs 中的细胞内 Ca 反应、线粒体功能和 ROS 的产生。在用 EPA 处理后，尽管细胞中的谷胱甘肽、谷胱甘肽过氧化物酶、细胞数量和细胞活力进一步降低，但 DBTRG 中的脂质过氧化、细胞凋亡、细胞死亡、半胱氨酸天冬氨酸蛋白酶-3、-8 和-9 水平进一步增加。总之，通过 EPA 处理激活 DBTRGs 中的 TRPM2 通道，进一步增强了 CiSP 的抗癌、凋亡和氧化作用。因此，通过 EPA 刺激 TRPM2 可能成为 CiSP 治疗神经胶质瘤肿瘤的有效手段。
