The activity of therapeutic molecular cluster Ag5 is dependent on oxygen level and HIF-1 mediated signalling
Year: 2024
Type: article
Abstract: 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.
Source: Redox Biology
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,900
Funders: Ministerio de Ciencia, Innovación y Universidades, Cancer Research UK, King's College London, European Commission, Xunta de Galicia, Fundación Bancaria Caixa d'Estalvis i Pensions de Barcelona, Medical Research Council, Engineering and Physical Sciences Research Council, European Regional Development Fund, Agencia Estatal de Investigación
Awards: G1030016813, G1105844351, G1175115578, G1218400627, G1258946664, G128883266, G1454588947, DTP Bid Led by University of Oxford, G1622782223, G1869016439, G210041235, G2238108805, G2262748287, G2281333282, G2601397997, G300979063, G3325634151, G34346518, G3480869486, G3681454997, G3802636750, G3876637791, G3979912349, G4042783231, G4092263876, G410571670, G425668148, Chemical biology tools for investigating the chemistry of cellular REDOX stress, G451917667, G4912030886, G491712853, G5080475149, G5195188938, G5267706263, G5404395142, G5522554483, G5539308778, G5705320215, G5967599077, G624877701, G692825579, G7084143925, G7805626310, G7863371703, G8497050386, G8764595522, G8941884509, G929308097
OpenAlex ID: W4401825583