Largazole is a potent class I selective histone deacetylase inhibitor prodrug with anticancer activity against solid tumors in preclinical models. Largazole possesses in vitro activity against glioblastoma multiforme (GBM) cells and sufficiently crosses the blood-brain barrier based on measurement of the active species, largazole thiol, to achieve therapeutically relevant concentrations in the mouse brain. The effective dose resulted in pronounced functional responses on the transcript level based on RNA sequencing and quantitative polymerase chain reaction after reverse transcription (RT-qPCR), revealing desirable expression changes of genes related to neuroprotection, including Bdnf and Pax6 upregulation, extending the applicability of largazole to the treatment of brain cancer and neurodegenerative disorders. The largazole-induced modulation of Pax6 unifies both activities, since Pax6 expression suppresses GBM proliferation and invasion and inversely correlates with GBM tumor grade, while it is also implicated in neurogenesis, neuronal plasticity, and cognitive ability. Our results suggest that largazole could be repurposed for diseases of the brain.

中文翻译：

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Largazole是一种可渗透脑的I类HDAC抑制剂，对胶质母细胞瘤和CNS疾病具有广泛的适用性。

Largazole是一种有效的I类选择性组蛋白脱乙酰基酶抑制剂前药，在临床前模型中对实体瘤具有抗癌活性。Largazole对多形性胶质母细胞瘤（GBM）细胞具有体外活性，并且基于对活性物种Largazole硫醇的测量，可以充分穿越血脑屏障，从而在小鼠大脑中达到治疗相关的浓度。有效剂量可在逆转录（RT-qPCR）后基于RNA测序和定量聚合酶链反应在转录水平上产生明显的功能反应，从而揭示与神经保护相关的基因（包括Bdnf和Pax6）的理想表达变化上调，扩大了Largazole在治疗脑癌和神经退行性疾病中的适用性。由于Pax6表达抑制GBM增殖和侵袭并与GBM肿瘤等级成反比，因此Largazole诱导的Pax6调节将这两种活性统一起来，同时还牵涉神经发生，神经元可塑性和认知能力。我们的研究结果表明，largazole可用于脑部疾病。