Department of Oncology, University of Oxford, Oxford, OX3 7DQ, UK.
Department of physiology and CIMUS Universidade de Santiago de Compostela, Spain.
Redox Biol. 2024 Oct;76:103326. doi: 10.1016/j.redox.2024.103326. Epub 2024 Aug 22.
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.
缺氧区域存在于大多数实体肿瘤中，已知其对治疗反应和患者预后有重大影响。Ag5 是一种最近报道的银分子簇，它可以抑制谷胱甘肽和硫氧还蛋白信号，从而限制细胞抗氧化能力。Ag5 处理在多种癌细胞系中显著降低细胞活力，对未转化细胞几乎没有影响。在缺氧条件下对氧化还原平衡的表征表明，活性氧和谷胱甘肽增加，尽管动力学不同。在模拟肿瘤微环境的一系列缺氧条件下观察到 Ag5 介导的显著存活率降低，但与常氧条件相比，这种效应降低。缺氧条件下对 Ag5 敏感性降低归因于 HIF-1 介导的信号转导，通过 PDK1/3 活性降低 PDH，并改变线粒体氧可用性。重要的是，在与放射抵抗相关的缺氧条件下，添加 Ag5 可显著增加辐射诱导的细胞死亡。总之，这些数据表明，Ag5 是一种有效的、针对癌症的药物，可与放射疗法联合使用。
