Verteporfin inhibits oxidative phosphorylation and induces cell death specifically in glioma stem cells
Verteporfin inhibits oxidative phosphorylation and induces cell death specifically in glioma stem cells
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DOI：
10.1111/febs.15187
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发表时间：
2020-01-09
期刊：
影响因子：
5.4
通讯作者：
Okada, Masashi
中科院分区：
文献类型：
--
作者：
Kuramoto, Kenta;Yamamoto, Masahiro;Okada, Masashi
多形性胶质母细胞瘤（GBM）是成人中最恶性的原发性脑肿瘤。由于胶质瘤干细胞（GSCs）与治疗耐药性以及GBM的发生和复发有关，因此针对GSCs的治疗被认为对GBM的长期生存有效。一些报道表明，癌症干细胞的氧化磷酸化（OXPHOS）对它们的存活很重要；然而，GSCs对OXPHOS的需求尚不清楚。很少有有效和安全的药物靶向GSC线粒体可用于临床设置。在这项研究中，我们证明了与等基因分化的GSCs相比，GSCs具有较高的OXPHOS活性，并且GSC的存活依赖于它们的OXPHOS活性。值得注意的是，我们发现复合物III和IV具有广阔的治疗窗口，并且与分化的GSCs相比，复合物III和IV的线粒体dna编码成分的表达水平在GSCs中升高。此外，我们对美国食品和药物管理局（fda）批准的靶向GSC线粒体的药物进行了搜索，结果显示，被批准用于黄斑变性的药物verteporfin （Visudyne (R)）是一种新的GSC特异性细胞毒化合物，可降低OXPHOS活性。重要的是，维替波芬的细胞毒作用是特异性的，对正常细胞没有任何毒性，大约200 nm的IC50比人体最大血药浓度低10倍。总的来说，这些发现表明，GSCs的高线粒体OXPHOS是一种潜在的gsc特异性脆弱性，临床可用的药物，如维替波芬，可能成为新的gsc特异性细胞毒性药物。
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 (R)), 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.