Glioblastoma multiforme (GBM) is the most malignant primary brain tumour in adults. Since glioma stem cells (GSCs) are associated with therapeutic resistance as well as the initiation and recurrence in GBM, therapies targeting GSCs are considered to be effective for long-term survival in GBM. Several reports suggested that oxidative phosphorylation (OXPHOS) of cancer stem cells is important for their survival; however, the requirement of OXPHOS in GSCs remains unclear. Few effective and safe agents that target GSC mitochondria are available in clinical settings. In this study, we demonstrated that GSCs had high OXPHOS activity compared with isogenic differentiated GSCs and that GSC survival depended on their OXPHOS activity. Remarkably, we showed that complexes III and IV had broad therapeutic windows and that the expression levels of mitochondrial DNA-coded components of complexes III and IV were elevated in GSCs compared with differentiated GSCs. Moreover, our search of the Food and Drug Administration-approved drugs for those targeting GSC mitochondria revealed that verteporfin (Visudyne® ), a drug approved for macular degeneration, was a novel GSC-specific cytotoxic compound that reduced OXPHOS activity. Importantly, the cytotoxic effect of verteporfin was specific to GSCs without any toxicity to normal cells, and the IC50 of approximately 200 nm was ten times less than its maximum blood concentration in humans. Overall, these findings indicated that high mitochondrial OXPHOS of GSCs is a potential GSC-specific vulnerability and that clinically available drugs, such as verteporfin, might become novel GSC-specific cytotoxic agents.

中文翻译：

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Verteporfin抑制氧化磷酸化并特别在神经胶质瘤干细胞中诱导细胞死亡。

多形胶质母细胞瘤（GBM）是成人中最恶性的原发性脑肿瘤。由于神经胶质瘤干细胞（GSC）与治疗耐药性以及GBM的起始和复发相关，因此靶向GSC的疗法被认为对于GBM的长期生存有效。几篇报道表明，癌症干细胞的氧化磷酸化（OXPHOS）对它们的存活很重要。但是，尚不清楚GSC中对OXPHOS的要求。在临床环境中，很少有针对GSC线粒体的有效和安全的药物。在这项研究中，我们证明了与同基因分化的GSC相比，GSC具有较高的OXPHOS活性，GSC的存活取决于它们的OXPHOS活性。值得注意的是 我们显示，复合物III和IV具有广阔的治疗窗口，并且与分化的GSC相比，复合物III和IV中线粒体DNA编码的成分的表达水平有所提高。此外，我们在美国食品药品监督管理局（FDA）批准的针对GSC线粒体药物的搜索中发现，批准用于黄斑变性的维替泊芬（Visudyne®）是一种新型的GSC特异性细胞毒性化合物，可降低OXPHOS活性。重要的是，维替泊芬的细胞毒性作用是GSC特有的，对正常细胞没有任何毒性，约200 nm的IC50比其在人体中的最大血药浓度低十倍。总体而言，这些发现表明，GSC的高线粒体OXPHOS是GSC特有的潜在脆弱性，并且临床上可获得的药物，