Department of Neurosurgery, the First Hospital of China Medical University, NO.155, North Nanjing Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China.
Department of Neurosurgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Cell Oncol (Dordr). 2020 Jun;43(3):461-475. doi: 10.1007/s13402-020-00502-y. Epub 2020 Mar 23.
The iron-chelating agent di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) has been found to inhibit cell growth and to induce apoptosis in several human cancers. However, its effects and mechanism of action in glioma are unknown.
Human glioma cell line LN229 and patient-derived glioma stem cells GSC-42 were applied for both in vitro and in vivo xenograft nude mouse experiments. The anti-tumor effects of Dp44mT were assessed using MTS, EdU, TUNEL, Western blotting, qRT-PCR, luciferase reporter, chromatin immunoprecipitation and immunohistochemical assays.
We found that Dp44mT can upregulate the expression of the anti-oncogene N-myc downstream-regulated gene (NDRG)2 by directly binding to and activating the RAR-related orphan receptor (ROR)A. In addition, we found that NDRG2 overexpression suppressed inflammation via activation of interleukin (IL)-6/Janus kinase (JAK)2/signal transducer and activator of transcription (STAT)3 signaling.
Our data indicate that Dp44mT may serve as an effective drug for the treatment of glioma by targeting RORA and enhancing NDRG2-mediated IL-6/JAK2/STAT3 signaling.
铁螯合剂二吡啶酮 4,4-二甲基-3-硫代缩氨基脲（Dp44mT）已被发现可抑制多种人类癌症的细胞生长并诱导细胞凋亡。然而，其在神经胶质瘤中的作用和作用机制尚不清楚。
应用人神经胶质瘤细胞系 LN229 和患者来源的神经胶质瘤干细胞 GSC-42 进行体外和体内异种移植裸鼠实验。使用 MTS、EdU、TUNEL、Western blot、qRT-PCR、荧光素酶报告、染色质免疫沉淀和免疫组织化学检测评估 Dp44mT 的抗肿瘤作用。
我们发现 Dp44mT 可以通过直接结合并激活 RAR 相关孤儿受体（ROR）A 而上调抑癌基因 N-myc 下游调节基因（NDRG）2 的表达。此外，我们发现 NDRG2 过表达通过激活白细胞介素（IL）-6/Janus 激酶（JAK）2/信号转导和转录激活因子（STAT）3 信号通路抑制炎症。
我们的数据表明，Dp44mT 可能通过靶向 RORA 并增强 NDRG2 介导的 IL-6/JAK2/STAT3 信号通路，成为治疗神经胶质瘤的有效药物。
