Glioblastoma is the most common primary malignant brain tumor in adults. Despite aggressive treatment, outcomes remain poor with few long-term survivors. Therefore, considerable effort is being made to identify novel therapies for this malignancy. Targeting tumor metabolism represents a promising therapeutic strategy and activation of fatty acid oxidation (FAO) has been identified as a central metabolic node contributing toward gliomagenesis. Perhexiline is a compound with a long clinical track record in angina treatment and commonly described as an FAO inhibitor. We therefore sought to determine whether this compound might be repurposed to serve as a novel therapy in glioblastoma. Perhexiline demonstrated potent in vitro cytotoxicity, induction of redox stress and apoptosis in a panel of glioblastoma cell lines. However, the antitumor activity of perhexiline was distinct when compared with the established FAO inhibitor etomoxir. By evaluating mitochondrial respiration and lipid dynamics in glioblastoma cells following treatment with perhexiline, we confirmed this compound did not inhibit FAO in our models. Using in silico approaches, we identified FYN as a probable target of perhexiline and validated the role of this protein in perhexiline sensitivity. We extended studies to patient samples, validating the potential of FYN to serve as therapeutic target in glioma. When evaluated in vivo, perhexiline demonstrated the capacity to cross the blood–brain barrier and antitumor activity in both flank and orthotopic glioblastoma models. Collectively, we identified potent FYN-dependent antitumor activity of perhexiline in glioblastoma, thereby, representing a promising agent to be repurposed for the treatment of this devastating malignancy.

中文翻译：

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Perhexiline 在胶质母细胞瘤中表现出 FYN 介导的抗肿瘤活性

胶质母细胞瘤是成人中最常见的原发性恶性脑肿瘤。尽管积极治疗，结果仍然很差，很少有长期幸存者。因此，正在做出相当大的努力来确定这种恶性肿瘤的新疗法。靶向肿瘤代谢是一种很有前景的治疗策略，脂肪酸氧化 (FAO) 的激活已被确定为促进神经胶质瘤生成的中心代谢节点。Perhexiline 是一种在心绞痛治疗中具有长期临床记录的化合物，通常被描述为 FAO 抑制剂。因此，我们试图确定这种化合物是否可以重新用作胶质母细胞瘤的新疗法。Perhexiline 在一组胶质母细胞瘤细胞系中显示出有效的体外细胞毒性、氧化还原应激诱导和细胞凋亡。然而，与已建立的 FAO 抑制剂 etomoxir 相比，perhexiline 的抗肿瘤活性是不同的。通过评估用 perhexiline 治疗后胶质母细胞瘤细胞中的线粒体呼吸和脂质动力学，我们证实该化合物在我们的模型中不抑制 FAO。使用计算机方法，我们将 FYN 确定为 perhexiline 的可能目标，并验证了该蛋白质在 perhexiline 敏感性中的作用。我们将研究扩展到患者样本，验证了 FYN 作为神经胶质瘤治疗靶点的潜力。在体内评估时，perhexiline 在侧翼和原位胶质母细胞瘤模型中证明了穿越血脑屏障的能力和抗肿瘤活性。总的来说，我们在胶质母细胞瘤中鉴定了 perhexiline 的有效 FYN 依赖性抗肿瘤活性，从而，