Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA, USA.
Department of Pathology, Microbiology and Immunology, School of Veterinary Medicine, University of California, Davis, CA, USA.
Biomed Pharmacother. 2021 Jan;133:111058. doi: 10.1016/j.biopha.2020.111058. Epub 2020 Dec 8.
Glioblastoma Multiforme (GBM) tumors contain a small population of glioma stem-like cells (GSCs) among the various differentiated GBM cells (d-GCs). GSCs drive tumor recurrence, and resistance to Temozolomide (TMZ), the standard of care (SoC) for GBM chemotherapy. In order to investigate a potential link between GSC specific mitochondria function and SoC resistance, two patient-derived GSC lines were evaluated for differences in their mitochondrial metabolism. In both the lines, GSCs had significantly lower mitochondrial -content, and -function compared to d-GCs. In vitro, the standard mitochondrial-specific inhibitors oligomycin A, antimycin A, and rotenone selectively inhibited GSC proliferation to a greater extent than d-GCs and human primary astrocytes. These findings indicate that mitochondrial inhibition can be a potential GSC-targeted therapeutic strategy in GBM with minimal off-target toxicity. Mechanistically the standard mitochondrial inhibitors elicit their GSC-selective cytotoxic effects through the induction of apoptosis or autophagy pathways. We tested for GSC proliferation in the presence of 3 safe FDA-approved drugs--trifluoperazine, mitoxantrone, and pyrvinium pamoate, all of which are also known mitochondrial-targeting agents. The SoC GBM therapeutic TMZ did not trigger cytotoxicity in glioma stem cells, even at 100 μM concentration. By contrast, trifluoperazine, mitoxantrone, and pyrvinium pamoate exerted antiproliferative effects in GSCs about 30-50 fold more effectively than temozolomide. Thus, we hereby demonstrate that FDA-approved mitochondrial inhibitors induce GSC-selective cytotoxicity, and targeting mitochondrial function could present a potential therapeutic option for GBM treatment.
多形性胶质母细胞瘤（GBM）肿瘤在各种分化的 GBM 细胞（d-GC）中存在一小部分胶质母细胞瘤干细胞（GSCs）。GSCs 驱动肿瘤复发，并对替莫唑胺（TMZ）产生耐药性，TMZ 是 GBM 化疗的标准治疗方法（SoC）。为了研究 GSC 特异性线粒体功能与 SoC 耐药性之间的潜在联系，评估了两种患者来源的 GSC 系在其线粒体代谢方面的差异。在这两种系中，GSCs 的线粒体含量和功能明显低于 d-GC。在体外，标准的线粒体特异性抑制剂寡霉素 A、antimycin A 和鱼藤酮选择性地抑制 GSC 增殖的程度大于 d-GC 和人原代星形胶质细胞。这些发现表明，线粒体抑制可能是 GBM 的一种潜在的 GSC 靶向治疗策略，其脱靶毒性最小。从机制上讲，标准的线粒体抑制剂通过诱导细胞凋亡或自噬途径来发挥其对 GSC 的选择性细胞毒性作用。我们在存在 3 种安全的 FDA 批准药物的情况下测试了 GSC 的增殖，这 3 种药物分别是三氟拉嗪、米托蒽醌和吡喹酮，它们都是已知的线粒体靶向药物。SoC GBM 治疗药物 TMZ 即使在 100μM 浓度下也不会引发神经胶质瘤干细胞的细胞毒性。相比之下，三氟拉嗪、米托蒽醌和吡喹酮对 GSCs 的增殖抑制作用比替莫唑胺有效 30-50 倍。因此，我们在此证明 FDA 批准的线粒体抑制剂诱导 GSC 选择性细胞毒性，靶向线粒体功能可能为 GBM 治疗提供一种潜在的治疗选择。
