最多等待 10 秒，若超时请稍后重试。
Rui-Jia Wen, Xin Dong, Hao-Wen Zhuang, Feng-Xiang Pang, Shou-Chang Ding, Nan Li, Yong-Xin Mai, Shu-Ting Zhou, Jun-Yan Wang, Jin-Fang Zhang
Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, P.R. China; Cancer center, Shenzhen Hospital (Futian) of Guangzhou University of Chinese Medicine, Shenzhen, 518000, P.R. China.
Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, P.R. China; The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, 510405, P.R. China.
Phytomedicine. 2023 Jul 25;116:154881. doi: 10.1016/j.phymed.2023.154881. Epub 2023 May 13.
Osteosarcomas (OS) is a kind of malignant bone tumor which occurs primarily in children and adolescents, and the clinical therapeutics remain disappointing. As a new programmed cell death, ferroptosis is characterized by iron dependent and intracellular oxidative accumulation, which provides a potential alternative intervene for the OS treatment. Baicalin, a major bioactive flavone derived from traditional Chinese medicine Scutellaria baicalensis, has been proved to have anti-tumor properties in OS. Whether ferroptosis participated in the baicalin mediated anti-OS activity is an interesting project.
To explore the pro-ferroptosis effect and mechanisms of baicalin in OS.
METHODS/STUDY DESIGN: Pro-ferroptosis effect of baicalin on cell death, cell proliferation, iron accumulation, lipid peroxidation production was determined in MG63 and 143B cells. The levels of glutathione (GSH), oxidized (GSSG) glutathione and malondialdehyde (MDA) were determined by enzyme linked immunosorbent assay (ELISA). The expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2), Glutathione peroxidase 4 (GPX4) and xCT were detected by western blot in baicalin-mediated ferroptosis regulation. In vivo, a xenograft mice model was adopted to explore the anticancer effect of baicalin.
In the present study, it was found that baicalin significantly suppress tumor cell growth in vitro and in vivo. By promoting the Fe accumulation, ROS formation, MDA production and suppressing the ratio of GSH/GSSG, baicalin was found to trigger ferroptosis in OS and ferroptosis inhibitor ferrostatin-1 (Fer-1) successfully reversed these suppressive effects, indicating that ferroptosis participated in the baicalin mediated anti-OS activity. Mechanistically, baicalin physically interacted with Nrf2, a critical regulator of ferroptosis, and influenced its stability via inducing ubiquitin degradation, which suppressed the Nrf2 downstream targets GPX4 and xCT expression, and led to stimulating ferroptosis.
Our findings for the first time indicated that baicalin exerted anti-OS activity through a novel Nrf2/xCT/GPX4-dependent ferroptosis regulatory axis, which hopefully provides a promising candidate for OS treatment.
骨肉瘤（OS）是一种主要发生在儿童和青少年的恶性骨肿瘤，其临床治疗效果仍不尽如人意。铁死亡作为一种新的程序性细胞死亡方式，其特征是铁依赖性和细胞内氧化积累，为骨肉瘤的治疗提供了一种潜在的替代干预方法。黄芩素是一种源自中药黄芩的主要生物活性黄酮，已被证明具有骨肉瘤的抗肿瘤特性。黄芩素是否参与了铁死亡介导的抗骨肉瘤活性是一个有趣的项目。
探讨黄芩素在骨肉瘤中的促铁死亡作用及其机制。
方法/研究设计：在 MG63 和 143B 细胞中，确定黄芩素对细胞死亡、细胞增殖、铁积累、脂质过氧化产物的促铁死亡作用。通过酶联免疫吸附试验（ELISA）测定谷胱甘肽（GSH）、氧化（GSSG）谷胱甘肽和丙二醛（MDA）的水平。通过 Western blot 检测黄芩素介导的铁死亡调节中核因子红细胞 2 相关因子 2（Nrf2）、谷胱甘肽过氧化物酶 4（GPX4）和 xCT 的表达水平。在体内，采用异种移植小鼠模型探讨黄芩素的抗癌作用。
本研究发现黄芩素在体外和体内均显著抑制肿瘤细胞生长。通过促进铁积累、ROS 形成、MDA 产生和抑制 GSH/GSSG 比值，黄芩素被发现可引发骨肉瘤中的铁死亡，铁死亡抑制剂 Fer-1 成功逆转了这些抑制作用，表明铁死亡参与了黄芩素介导的抗骨肉瘤活性。机制上，黄芩素与铁死亡的关键调节因子 Nrf2 发生物理相互作用，并通过诱导泛素降解影响其稳定性，从而抑制 Nrf2 下游靶标 GPX4 和 xCT 的表达，导致铁死亡的刺激。
我们的研究结果首次表明，黄芩素通过一种新的 Nrf2/xCT/GPX4 依赖性铁死亡调节轴发挥抗骨肉瘤活性，有望为骨肉瘤的治疗提供一种有前途的候选药物。
