School of Medicine, University of Leeds, Leeds LS2 9JT, UK.
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK.
Sci Transl Med. 2018 Aug 15;10(454). doi: 10.1126/scitranslmed.aar2718.
Pharmacological inhibition of uncontrolled cell growth with small-molecule inhibitors is a potential strategy for treating glioblastoma multiforme (GBM), the most malignant primary brain cancer. We showed that the synthetic small-molecule KHS101 promoted tumor cell death in diverse GBM cell models, independent of their tumor subtype, and without affecting the viability of noncancerous brain cell lines. KHS101 exerted cytotoxic effects by disrupting the mitochondrial chaperone heat shock protein family D member 1 (HSPD1). In GBM cells, KHS101 promoted aggregation of proteins regulating mitochondrial integrity and energy metabolism. Mitochondrial bioenergetic capacity and glycolytic activity were selectively impaired in KHS101-treated GBM cells. In two intracranial patient-derived xenograft tumor models in mice, systemic administration of KHS101 reduced tumor growth and increased survival without discernible side effects. These findings suggest that targeting of HSPD1-dependent metabolic pathways might be an effective strategy for treating GBM.
用小分子抑制剂抑制不受控制的细胞生长是治疗多形性胶质母细胞瘤（GBM）的一种潜在策略，GBM 是最恶性的原发性脑癌。我们发现合成的小分子 KHS101 可促进多种 GBM 细胞模型中的肿瘤细胞死亡，而与肿瘤亚型无关，且不会影响非癌细胞系的活力。KHS101 通过破坏线粒体伴侣热休克蛋白家族 D 成员 1（HSPD1）发挥细胞毒性作用。在 GBM 细胞中，KHS101 促进调节线粒体完整性和能量代谢的蛋白质聚集。在 KHS101 处理的 GBM 细胞中，线粒体生物能量和糖酵解活性被选择性地损害。在两种小鼠颅内患者来源的异种移植肿瘤模型中，全身性给予 KHS101 可减少肿瘤生长并提高存活率，而无明显副作用。这些发现表明，靶向 HSPD1 依赖性代谢途径可能是治疗 GBM 的有效策略。
