Department of Neurosurgery, Shenzhen Key Laboratory of Neurosurgery, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, China.
Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
Phytother Res. 2021 Jun;35(6):3390-3405. doi: 10.1002/ptr.7061. Epub 2021 Apr 15.
Glioblastoma multiforme (GBM) is the most frequent, lethal, and aggressive tumor of the central nervous system in adults. In this study, we found for the first time that moschamindole (MCD), a rare phenolic amide with 8/6/6/5/5 rings, is a major bioactive constituent derived from Phragmites communis Trin (Poaceae) that exhibits a potential cytotoxic effect on both TMZ-resistant GBM cell lines and xenograft models. MCD-induced intrinsic apoptosis signals and mitochondrial dysfunction were confirmed by cell cycle arrest, caspase-3/7 activation, and membrane potential depolarization. Furthermore, investigations exploring the mechanism showed that MCD specifically inhibits Mia40-mediated oxidative folding of mitochondrial intermembrane space (IMS) proteins via PCR assay and immunoblot analysis. MCD relies on its positive charge to associate with mitochondrial oxidative respiration, thus blocking energy metabolism and inducing apoptosis. Overexpression and upregulation of Mia40 were proven to reverse MCD-induced apoptosis and were correlated with the chemoresistance of GBM in vitro and in vivo, respectively. Taken together, our study demonstrates that Mia40 is a potential target of the chemoresistance of glioblastoma and suggests that MCD might be a potential agent for the individualized treatment of chemoresistant GBM based on mitochondrial metabolic characteristics and Mia40 expression.
多形性胶质母细胞瘤（GBM）是成人中枢神经系统中最常见、最致命和最具侵袭性的肿瘤。在这项研究中，我们首次发现，来源于香蒲（香蒲科）的罕见酚酰胺 moschamindole（MCD），具有 8/6/6/5/5 个环，是一种主要的生物活性成分，对 TMZ 耐药的 GBM 细胞系和异种移植模型均表现出潜在的细胞毒性作用。通过细胞周期阻滞、caspase-3/7 激活和膜电位去极化证实了 MCD 诱导的内在凋亡信号和线粒体功能障碍。此外，通过 PCR 检测和免疫印迹分析，研究探索了机制，表明 MCD 通过特定方式抑制 Mia40 介导的线粒体间室（IMS）蛋白的氧化折叠。MCD 依靠其正电荷与线粒体氧化呼吸结合，从而阻断能量代谢并诱导细胞凋亡。Mia40 的过表达和上调被证明可以逆转 MCD 诱导的凋亡，并与体外和体内 GBM 的化疗耐药性分别相关。综上所述，我们的研究表明 Mia40 是胶质母细胞瘤化疗耐药性的一个潜在靶点，并提示 MCD 可能是一种基于线粒体代谢特征和 Mia40 表达的针对化疗耐药性 GBM 的个体化治疗的潜在药物。
