The activity of therapeutic molecular cluster Ag5 is dependent on oxygen level and HIF-1 mediated signalling

Journal article

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.

Authors: Twigger, S; Dominguez, B; Porto, V; Hacker, L; Chalmers, A

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Elsevier
• Journal: Redox Biology
• Volume: 76
• Article number: 103326
• Publication date: 2024-08-22
• Acceptance date: 2024-08-21
• DOI: 10.1016/j.redox.2024.103326
• EISSN: 2213-2317
• Language: English
• Keywords: redox; radiation; hypoxia; Ag5; HIF-1