Regions of hypoxia occur in most solid tumours and are known to significantly impact therapy response and patient prognosis. Ag5 is a recently reported silver molecular cluster which inhibits both glutathione and thioredoxin signalling therefore limiting cellular antioxidant capacity. Ag5 treatment significantly reduces cell viability in a range of cancer cell lines with little to no impact on non-transformed cells. Characterisation of redox homeostasis in hypoxia demonstrated an increase in reactive oxygen species and glutathione albeit with different kinetics. Significant Ag5-mediated loss of viability was observed in a range of hypoxic conditions which mimic the tumour microenvironment however, this effect was reduced compared to normoxic conditions. Reduced sensitivity to Ag5 in hypoxia was attributed to HIF-1 mediated signalling to reduce PDH via PDK1/3 activity and changes in mitochondrial oxygen availability. Importantly, the addition of Ag5 significantly increased radiation-induced cell death in hypoxic conditions associated with radioresistance. Together, these data demonstrate Ag5 is a potent and cancer specific agent which could be used effectively in combination with radiotherapy.

中文翻译：

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治疗性分子簇 Ag5 的活性取决于氧水平和 HIF-1 介导的信号传导


缺氧区域发生在大多数实体瘤中，并且已知会显着影响治疗反应和患者预后。 Ag5 是最近报道的一种银分子簇，它抑制谷胱甘肽和硫氧还蛋白信号传导，从而限制细胞的抗氧化能力。 Ag5 处理显着降低了一系列癌细胞系的细胞活力，对非转化细胞几乎没有影响。缺氧条件下氧化还原稳态的表征表明活性氧和谷胱甘肽有所增加，尽管动力学不同。在一系列模拟肿瘤微环境的低氧条件下观察到 Ag5 介导的活力显着丧失，但与常氧条件相比，这种效应有所减弱。缺氧时对 Ag5 的敏感性降低归因于 HIF-1 介导的信号传导，通过 PDK1/3 活性和线粒体氧利用率的变化来减少 PDH。重要的是，Ag5 的添加显着增加了与放射抗性相关的缺氧条件下放射诱导的细胞死亡。总之，这些数据表明 Ag5 是一种有效的癌症特异性药物，可以有效地与放射疗法结合使用。